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The efficacy of applying some plants and herbs in cancer therapy for humans and animals – A comprehensive review

The efficacy of applying some plants and herbs in cancer therapy for humans and animals – A... Ann. Anim. Sci., Vol. 23, No. 2 (2023) 315–338 DOI: 10.2478/aoas-2022-0078 The efficacy of applying some planTs and herbs in cancer Therapy for humans and animals – a comprehensive review 1♦ 2 3 4 5 6 Mohamed E. Abd El-Hack , Manal A. Alfwuaires , Muthana M. Jghef , Asmaa F. Khafaga , Sameh A. Abdelnour , Mahmoud Abdel-Hamid , 1 2 7 8,9♦ 10 11 Mahmoud Alagawany , Abdulmohsen I. Algefare , Mashael M. Alnamshan , Mohamed S. Imam , Mohammed Gamal , Ahmad E. Elesawi , 12,13 Mohammad H. Abukhalil Poultry Department, Faculty of Agriculture, Zagazig University, Zagazig 44511, Egypt Department of Biological Sciences, Faculty of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia Department of Radiology, College of Medical Technology, Al-Kitab University, Kirkuk 36001, Iraq Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina 22758, Egypt Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig 44519, Egypt Dairy Science Department, Faculty of Agriculture, Cairo University, Giza, 12613, Egypt Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia Department of Pharmacy Practice, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia Department of Clinical Pharmacy, National Cancer Institute, Cairo University, Egypt Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Alshaheed Shehata Ahmad Hegazy St., 62514, Beni-Suef, Egypt Project Management and Sustainable Development Department, Arid Land Agriculture Research Institute, City of Scientific Research and Technological Applications, 21934, Alexandria, Egypt Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma’an 71111, Jordan Department of Biology, College of Science, Al-Hussein Bin Talal University, Ma’an 71111, Jordan Corresponding authors: Mohamed S. Imam: soliman@su.edu.sa, Mohamed E. Abd El-Hack: dr.mohamed.e.abdalhaq@gmail.com abstract cancer is a challenging ailment and represents the main reason for death worldwide for humans and animals. although great develop - ments have hindered cancer progression, several adverse effects are associated with modern chemotherapy. natural remedies, such as the usage of medicinal plant or their products in cancer treatment, may decrease prejudicial side properties. recently, the modern research scheme and innovative screening practices for herbs or plants have enabled phytochemical discovery for the prevention and treatment of cancer. This criticism highlights herbs such as acacia, basil, black seeds, cedar, castus, ficus, garlic, ginger, indigo, onion, pomegranate, quince, and thyme, promising anticancer effects. The present review also revealed the mode of action of each herb as anticancer effects at level in vitro and in vivo studies. The item also totalizes the vital mechanisms and signaling molecules involved in preventing cancer diseases. This will fill the investigation gap in the exploration of using natural molecules and encourage researchers in clinical trials of anticancer agents from herbs for humans and animals. Key words: herbs, plants, anticancer, tumor, therapy, natural remedies Most people (70–80%) in the developing world de- (WHO, 2019). Reports documented that the annual world pend on complementary or alternative medicine (World market of alternative herbal medications was valued at Health Organization, 2000). The World Health Organiza- $90 billion in 2015, while it was $200 000 and 1 300 000 tion (WHO) outlines alternative medicine as the entirety in 2007 and 2009, respectively (WHO, 2019). There are of the knowledge, practices and skills, according to the many traditional medicines used worldwide, from Islam- experiences, theories, and views indigenous to various ic medicine and Tibbs Nabawi or medicine of the Prophet cultures, whether justifiable or not, applied in the main - (AlRawi and Fetters, 2012), that include herbs and plants tenance of health as well as in the diagnosis, prevention, of various biological events that may be beneficial for enhancement or therapy of mental and physical diseases. human health. In the current review, we will discuss the Traditional or alternative medicine differs significantly anticancer activity of some herbs and plants declared in from culture to culture and region to region, as they are the holy Quran and prophetic Hadith. affected by many features including history, culture, per- Recently, several scientific interpretations mentioned sonal attitudes, and philosophy (WHO, 2000). Based on that herbal remedy is an important alternative tactic in the WHO reports, the market value of herbal medications the therapy of cancer (Dhanjal et al., 2021; Rana et al., has also augmented tremendously in the last few years 2021). These significant properties of some herbs in can- 316 M.E. Abd El-Hack et al. cer therapy might be associated with their anticancer a masking agent for bitter substances (Gebriel, 2011). As profits and other related pharmacological events, which reported by Roothaert and Franzel (2001), the usage of have established a prodigious deal of consideration for root decoction incorporated with leaves of Combretum their health usefulness (Roy et al., 2010; Khan et al., glutinosum and curdled milk presented strong diuresis. 2022). Moreover, herbal therapy preserves individuals’ As reported by various researchers, the anticancer activi- fertility and health, cures diseases, and even evades, ties of A. seyal are presented in Table 1. inhibits, or reduces cancer progress without bringing toxicity or side effects (Khan et al., 2022; Muhammad Table 1. The potentiality of anticancer activities of Acacia seyal et al., 2022). Studies indicated that more than 60% of based on the in vivo and in vitro studies cancer patients used herbs in their cancer therapy pro- Extract/active Study Cancer cell Mechanisms tocols (Khan et al., 2022; Muhammad et al., 2022; Tan References ingredient type type of action et al., 2022). So, the present review article hypothesizes Hydroethanolic In vitro MCF-7 cells- ↑Cytotoxicity (Zingue et that using certain plants, herbs or their derivatives has extract breast cancer al., 2018) a positive role in modern cancer therapy. In this criticism, cells we deliberate the uses of some herbs in the embattled Hydroethanolic In vivo 7,12-dimeth- ↓Tumor (Zingue et therapy of cancer disease in various kinds of tumor cells extract ylbenza-anthra- progression al., 2018) based on anti-apoptotic or antioxidant agents, as well as ceneDMBA- induced breast facts on their toxicity and safety. hyperplasia Lectin In vitro Hepatocellular ↓Bcl-2, ↑P53 (Patel et al., cancer cell apoptosis carcinoma 2014) Carcinogenesis is an imbalance between cell de- (HepG-2), velopment and cell death that accelerates cancer cell HCT-116 proliferation. Cancer can be observed as the result of (colorectal carcinoma) and a sequence of genetic fluctuations during which a nor - MCF-7 (breast mal cell is converted into a malignant one, while evasion cancer) of cell death is one of the indispensable fluctuations in Methanolic In vitro A549 (lung ↑Cytotoxicity (El-Hallouty a cell that causes this malignant transmutation (Hanahan extract of leaves carcinoma) et al., 2015) and Weinberg, 2000). Hence, inhibition of apoptosis or and branches and HepG-2 its resistance is vigorous in carcinogenesis progression. (hepatocellular carcinoma) Caspases are fundamental agents in the machinery of ap- optosis, as they are both the initiators and executioners. Specifically, caspase enzymes can be activated through three pathways. The two generally described initiation Zingue et al. (2018) evaluated the in vivo and in vitro tracks are irrelevant (or death receptor) and intrinsic (or anticancer properties of hydroethanolic extract of A. seyal mitochondrial) tracks of apoptosis. on breast cancer. The cytotoxicity action of A. seyal stem Consequently, both tracks ultimately lead to a com- bark extract was estimated via a resazurin reduction test munal track or the execution stage of the apoptosis pro- in different cell lines. The A. seyal extract meaningfully cess. The third track’s less well-recognized initiation is decreased tumor incidence in rats by 62.1% and 65.8% the intrinsic endoplasmic reticulum pathway (O’Brien for 150 mg and 300 mg/kg doses, respectively. They also and Kirby, 2008). Generally, the mechanisms by which reported that the A. seyal extract showed IC50 of 100 in cancer cells evade apoptosis may be regarded as the in- MCF-7 cells after 24 h. Moreover, A. seyal showed sub- terrupted equilibrium of pro-apoptotic and anti-apoptotic stantial protection against DMBA-brought breast hyper- mediators, reduced caspase function and weakened death plasia in rats, with an optimum result at 300 mg/kg level. receptor signaling. This imbalance between pro-apoptot- Likewise, the cytotoxicity of the recombinant lectin ic and anti-apoptotic elements promoted the survival and extracted from A. sayel was executed on MCF-7 (breast proliferation of cancer cells (Taylor et al., 2008). cancer), HepG-2 (hepatocellular carcinoma), HEP-2 (lar- ynx cancer) and HCT-116 (colon cancer) as reported by anticancer activities of some herbs and plants Patel et al. (2014). The purified lectin displayed a note- Acacia (Acacia seyal) worthy cytotoxic property on MCF-7 cells, with the IC In sub-Saharan Africa, the traditional system of medi- values for 100 µg/ml and 250 µg/ml for HepG-2 cells and cine Acacia seyal is used to treat several ailments such MCF-7, respectively. According to the previous work, the as dermatosis, infertility, and cancers. The stem is also lectin isolated form Acacia has beneficial anticancer prop- widely used to treat fungal infections, mainly genital erties, especially at a high dose of 100 µg/ml. Some of yeast infections and as chewing sticks with antimicrobial the mechanisms involved are suppression of the Bcl-2 and activity. A bark decoction is applied alongside leprosy and decreased expression of P53. Hence, A. sayel established dysentery diseases; as a stimulant and purgative agent; as possible cytotoxic events on the cancer cells HCT-116 an aphrodisiac with cytotoxic activity; as a pharmaceuti- (colorectal carcinoma), MCF-7 (breast adenocarcinoma), cal constituent in making emulsions and torches and as A549 (lung carcinoma) and HepG2 (hepatocellular carci- Efficacy of some plants and herbs in cancer therapy for humans and animals 317 noma). El-Hallouty et al. (2015) also confirmed the anti- ber of papillomas/mouse) and the deceased proportion of cancer activities of A. sayel at 1000 µg/ml against several tumor-bearing mice (Zeggwagh et al., 2007; Zarlaha et cancer cells, although the authors reported low activities al., 2014). that were less than 75% cytotoxicity. In an in vitro experiment, Karthikeyan et al. (1999) studied the anticancer activity of O. sanctum alongside Basil: sweet basil (Ocimum basilicum) and holy basil HFS cells (human fibrosarcoma cells). They found that (Ocimum sanctum) ethanolic extract of O. sanctum produced cytotoxic- Basil (family Lamiae) is a prevalent herb incorporat- ity impacts on HFS cells at 50 µg/ml levels. The cells ed with countless varieties of food preparations in Medi- exhibited shrunken cytoplasm, condensed nuclei, DNA terranean diets. For a long time, basil has been considered fragmentation, augmented lipid peroxidation levels, and one of the main essential oils-producing species connected depleted intracellular glutathione for the cytological at- to the genus Ocimum (Mohammadi et al., 2014). Moreo- tributes. Moreover, treating mice bearing solid sarcoma ver, studies have shown that basil and its extracts are also tumors with ethanolic and aqueous extracts of O. sanc- applied in the industrial trade, including pharmaceutical tum interceded a substantial decrease in tumor volume and cosmetic products (Grayer et al., 2002). Many studies and an augment in lifespan (Sridevi et al., 2016). Based have been published on the biological activities, including on the potential previous effects, it is clear that O. sanc- antibacterial, anti-inflammatory and antioxidant actions of tum extract has anticancer activity. basil essential oils and its components (Liu et al., 2012; Sridevi et al. (2016) studied the properties of alco- Mehana et al., 2020; Khafaga et al., 2019). Basil essential holic root extract of O. sanctum in NCI-H460 (human oils present several active components, such as eugenol, non-small cell lung carcinoma cell) by the generation geraniol, linalool, methyl chavicol and thymol, showing of ROS, cell viability assay, mitochondrial membrane several biological properties. Many investigated the anti- potential and apoptotic morphological changes. Admin- microbial action of eugenol with analgesic action for hu- istration of NCI-H460 cells with 150 μg/ml of O. sanc- mans (Koeduka et al., 2006) and the antioxidant action of tum extracts showed the lowest cell viability. Moreo- geraniol and linalool (Liu et al., 2012). ver, the O. sanctum extract (25–100μg/ml) presented a Others examined the usage of thymol, methyl chavi- substantial augment in ROS synthesis, inhibited cell col, and linalool for skin protection alongside all causes viability, increased apoptotic cell, loss of mitochon- of environmental skin aggressors and handling of dif- drial membrane potential, and colony-making abil- ferent dermatological syndromes (Huang et al., 2015). ity in NCI-H460 cells. It is interesting to note that O. Essential basil oils are also used in folklore medicine sanctum triggered loss of NCI-H460 cell, which is the to manage various human disorders such as cardiovas- potentiality of its anticancer activity. In another ex- cular and diabetes diseases (Zeggwagh et al., 2007). Ba- periment, Magesh et al. (2009) confirmed that O. sanc- sil has antioxidant, antimicrobial and antitumor ac- tum brings apoptosis in A549 cells via a mitochondrial tivities. Because basil is widespread worldwide, it is caspase-dependent way and hinders the in vivo (ani- easy to discover the potential activity of its essential mal model) development of Lewis lung carcinoma, oils. These biological properties of basil or its essential indicating that O. sanctum can be useful for treating oil might be attributed to its aromatic compounds and lung carcinoma as a chemo-preventive agent. Addi- phenolic acids (Zeggwagh et al., 2007; Zarlaha et al., tionally, the study implemented by Kwak et al. (2014) 2014). recommended that the anti-metastatic machinery of O. Taie and Radwan (2010) studied the upshot of the es- sanctum is interceded by repression of PI3K/Akt in sential oils of sweet basil obtained from Egypt, which osteopontin-treated lung cancer cells (NCI-H460). Ta- are extracted by hydro-distillation of the basil leaves. Re- ble 2 lists in vitro and in vivo studies that show basil’s sults showed the activity of the essential oils on a line of anticancer activities (O. basilicum). Ehrlich ascites carcinoma cells (EACC), where different Several scientific experiments indicated that O. ba- doses of the essential oils highly influenced the viability silicum extract or its essential oils showed cytotoxic- of these cancer cell lines by measuring the % of dead ity effects on MCF-7 or MDA-MB-231 via induction of cells. Mahmoud (2013) studied the anticancer activities apoptosis pathways, including caspase-3, bax, bcl-2, and of basil essential oils (in vitro and in vivo). The previ- p53 genes, as well as induced anaphase/telophase stag- ous study exhibited that incubating NB4 and HL-60 cells es along with F-actin aggregation (Arshad Qamar et with basil essential oils at levels of 25–200 μg/ml for 24 al., 2010; Behbahani, 2014; Mohammadi et al., 2014). h decreased these cells’ viability. It was indicated that the These consequences support the antiproliferative and basil essential oil (200 μg/ml) induced the highest HL-60 anticancer activities of O. basilicum extract against dead cell (82.33%), as mentioned by Mahmoud (2013). numerous types of cancer cell lines. Zarlaha et al. (2014) Moreover, administration of EACC with basil essential examined the antiproliferative action of ethanolic extract oils at levels of 25–200 μg/ml for 12 h decreased the vi- and the essential oil of O. basilicum alongside four vari- ability percentages of these cells. In vivo results showed ous cancer cell lines in humans: FemX cells (melanoma), that basil leaf extract chemo-preventive action was mani- HeLa cells (cervix adenocarcinoma), SKOV3 cells (hu- fest from the deceased tumor burden (the average num- man ovarian) and K562 cells (chronic myelogenous leu- 318 M.E. Abd El-Hack et al. kemia). The dominant elements of the extract are caffeic wide, such as southern Europe and the Middle Eastern and rosmarinic acids, while the most abundant elements Mediterranean (Khare, 2004). Seeds of N. sativa and in the essential oil are linalool, eugenol, and isoeugenol. their oil have been broadly applied for several culinary Those phytochemicals displayed noteworthy cytotoxic ac- or therapeutic applications. N. sativa has biological and tion alongside human ovarian cancer (SKOV3) cell lines. therapeutic activities as an antioxidant, antimicrobial, Curiously, caffeic acid was reported to be in the identical analgesic, anti-inflammatory, diuretic, renal protective, choice with cisplatin alongside the four cell lines displaying antihypertensive, antidiabetic, immunomodulatory, bron- substantial anticancer properties. At the same time, isoeuge- chodilating, gastroprotective, hepato-protective, and an- nol showed a higher cytotoxic effect than eugenol. Moreo- ticancer (El-Far, 2015; El-Far et al., 2017). Although they ver, depending on the in silico modeling experiments, the contain a complex mixture of several compounds, thy- isoeugenol molecule can efficiently constrain cyclooxyge- moquinone (TQ) is undoubtedly its major active ingredi- nase and lipoxygenase enzymatic action. Mechanisms of ent (Hajhashemi et al., 2004). TQ has been described to action of acacia and basil are illustrated in Figure 1. possess potent anti-inflammatory effects, such as in cases of encephalomyelitis, edema, colitis, and arthritis via the black seed (Nigella sativa) reduction of inflammatory prostaglandins and leukot - Nigella sativa seed (black cumin or black seed) is an rienes (Hajhashemi et al., 2004), and anti-tumoral activ- annual flowering herb found in many countries world- ity (El-Far, 2015) (Table 5). Table 2. The in vitro and in vivo studies showing the anticancer activities of basil (Ocimum basilicum) Extract/active Mechanisms Plant Study type Cancer cell type References ingredient of action Sweet Basil (Ocimum Essential oils (crude) In vitro A line Ehrlich ascites ↓Cell viability (Taie and Radwan, basilicum) carcinoma cells (EACC) 2010) Essential oils (crude) In vitro and in vivo Human promyelocytic In vitro: ↑cytotox- (Mahmoud, 2013) leukemia cell lines icity (HL-60 and NB4) and In vivo: Ehrlich ascites carcinoma ↓Tumor develop- cells, EACC (animal ment and tumor model cancer cells) volume of mice Methanolic extract In vitro Human breast cancer ↑Apoptosis (Arshad Qamar et al., and active compound cells (MCF-7 cell lines) 2010) (ursolic acid) Crude essential oils In vitro Human breast cancer ↑Apoptosis (Mohammadi et al., from leaves cells (MCF-7 cell lines) 2014) Crude essential oils In vitro MCF-7 and MDA- ↑Apoptosis (Behbahani, 2014) MB-231 (breast cancer cell lines) Ethanolic extract and In vitro HeLa cells (cervix ↑Cytotoxic (Zarlaha et al., 2014) the essential oil adenocarcinoma), FemX cells (melanoma), SKOV3 cells (human ovarian cancer) and K562 cells (chronic my- elogenous leukemia) Holy Basil Ethanolic and aqueous In vitro and in vivo HFS cells (human In vitro: (Karthikeyan et al., (O. sanctum) extract of the basil fibrosarcoma cells) Morphologically the 1999) leaves Sarcoma-180 cells showed con- densed nuclei and shrunken cytoplasm ↓intracellular GPx and increased ROS In vivo: ↓Tumor volume Ethanolic root extract In vitro NCI-H460 (non-small- ↓Cell viability (Sridevi et al., 2016) cell lung cancer cell ↓Colony forming lines) capacity Ethanolic root extract In vitro A549 cells (adenocarci- ↑Apoptosis (Magesh et al., 2009) nomas’ human alveolar basal epithelial cells) Ethanolic root extract In vitro NCI-H460 cell line ↓PI3K/Akt (Kwak et al., 2014) Efficacy of some plants and herbs in cancer therapy for humans and animals 319 Figure 1. Anti-cancer mechanisms of action of acacia and basil Table 5. Anticancer activities of C. speciosus Extract/active ingredient Study type Cancer cell type Mechanisms of action References Diosgenin In vitro HepG2, HL-60, Saos-2 Inhibition in the cell viability and (Selim and Al and MCF-7 induction of apoptosis Jaouni, 2016) Dioscin In vitro Hela Induction of apoptosis (Selim and Al Jaouni, 2016) Methanol and hexane extracts (leaves) In vitro HepG2, THP-1, and Inhibition of cell proliferation (Selim and Al WI-38 Jaouni, 2015) Costunolide In vitro and in silico MCF-7 and MDA- Induction of apoptosis and (Pitchai et al., MB-231 Inhibition in the cell viability 2014) (Roy and Manik- kam, 2015) Methanol extract (leaves) In vitro HepG2 Cell proliferation inhibition (Singh et al., using MTT 2016) In breast tissue, it has promoted apoptosis via acti- studies in xenograft mice model of HCT-116 colon can- vation of the p38 phosphorylation MDA-MB-231 xen- cer cells (Shoieb et al., 2003; Gali-Muhtasib et al., 2008). ograft mice (Woo et al., 2013). Also, other molecular in DLD-1 human colon cancer cells, TQ promoted the mechanisms, including the downregulation of Akt and reduction in the generation of ROS and phosphorylation XIAP that promoted the expression of caspase-3, Bax, of JNK and ERK and elevated activity of caspase-3 and apoptosis index factor (AIF), cytochrome c and p27 -7 (El-Najjar et al., 2010). Different animal models have genes in MCF-7 and breast cancer (MDA-MB-231) cells been used to investigate the molecular mechanisms and (Rajput et al., 2013). Furthermore, in vitro results showed potential therapeutic effects of TQ on hepatocellular an elevated expression of PPAR-γ activity and lower ex- carcinoma (HCC), such as rats, mice and rabbits (Nagi pression of some related apoptosis genes, including Bcl- and Almakki, 2009; Sayed-Ahmed et al., 2010; El- 2, Bcl-xL, and survival in breast cancer cells (Woo et al., Sayed, 2011; Elbarbry et al., 2012; Raghunandhakumar 2013). Other studies on lung cancer showed decreased et al., 2013; Ashour et al., 2014). In Sprague Dawley expression of LPS-induced NF-B expression (Jafri et al., rats, Al-Dalaen (2014), extensive studies have shown 2010). The bulk of scientific research on colon and colo- lowered activities of CYP1A1 and CYP2E1 in different rectal cancers in vivo and in vitro has been recently ad- tissues such as liver, lung and stomach tissues. Prostate dressed. In a study by Jrah-Harzallah et al. (2013) Wistar cancer in vitro data showed a reduction in androgen re- rats showed repressed DMH-induced oxidative stress and ceptors, E2F-1- and E2F-1-regulated proteins (Kaseb et colon tumorigenesis, confirming the results from other al., 2007). 320 M.E. Abd El-Hack et al. Hydroalcoholic extract, n-hexane, and ethyl acetate aqueous extract, were cytotoxic to MCF-7 cells at low fraction in vitro recent research showed a lowered viabil- concentrations and improved the antitumor property of ity of the ACHN cell in a dose- and time-dependent man- doxorubicin in breast cancer cells (MCF-7) (Mahmoud ner without considerable cytotoxicity in the slandered and Torchilin, 2013). Table 3 depicts different studies renal epithelial cell (Shahraki et al., 2015, 2016). Other that demonstrated the potential anticancer activities of black seed preparations, such as the lipid fraction and Nigella sativa. Table 3. Anticancer activities of Nigella sativa Extract/active ingredient Study type Cancer cell type Mechanisms of action References 1 2 3 4 5 TQ In vivo MDA-MB-231 xenograft mice ↑p38, ↑ROS (Woo et al., 2013) (breast cancer) In vivo MCF-7 and MDA-MB-231 ↓XIAP, ↓Akt , ↑p27, ↑caspase-3 ↑Bax, (Rajput et al., 2013) (xenograft breast cancer mice) ↑cytochrome c, ↑AIF, In vivo Lung cancer ↓LPS-induced NF- B expression (Jafri et al., 2010) In vivo Colon cancer ↓DMH-brought ROS and colon tumori- (Jrah-Harzallah, et al., genesis in Wistar rats 2013) In vivo Mice model of HCT-116 colon ↓growth of tumor cells (Gali-Muhtasib et al., cancer cells 2008) In vivo Colon cancer ↓DMH-induced colon cancer promotion (Jrah-Harzallah, et al., 2013) In vivo Colorectal cancer (HCT-116) cells ↑p21 expression (Shoieb et al., 2003) and osteosarcoma cells G1 phase cell cycle arrest In vivo Hepatocellular carcinoma ↑expression of p21 (Raghunandhakumar et ↓expression of cyclin D1, and E. al., 2013) ↓Cdk4, ↓Ki67, ↓PCNA in hepatic tissues of rat; ↓the cyclinD1, ↓cyclin E, ↓PCNA in NDEA-induced rats In vivo Male Wistar albino rats Restored DENA-induced depletion of (Sayed-Ahmed et al., glutathione, reduced hepatic enzyme 2010) activities including ↑CAT, ↑GPx, ↑GST, and down-regulation of some genes In vivo HepG2 cells G2/M phase cell cycle arrest (Ashour et al., 2014) ↓p50, ↓p65, ↓IL-8, ↓CXCR1, and ↓CXCR2, ↑caspase-9, ↑caspase-3, ↑PARP, ↑TRAIL, ↓NF-B, ↓Bcl-2 In vivo Sarcoma 80 xenograft mice Mixture with diosgenin ↓tumor mass (Das et al., 2012) ↓volume and ↑apoptosis In vitro MCF-7, MDA-MB-231 and ↑apoptosis (Woo et al., 2013) BT-474 (breast cancer cell lines) ↑caspases-8, ↑caspases-9, ↑caspases-7 ↑PPAR-γ, ↓Bcl-xL, ↓Bcl-2, and ↓survivin In vitro HTLV-I-negative T-cell Induced mitochondrial-mediated apopto- (Dergarabetian et al., lymphomas sis via generation of ↑ROS 2013) In vitro NCI-H460 and NCI-H146 cells Promoted apoptosis and suppressed the (Jafri et al., 2010) synthesis of ↓Gro-alpha and ↓ENA-78 In vitro Primary effusion lymphoma Induced mitochondrial-mediated apopto- (Hussain et al., 2011) sis and TRAIL via deactivation of↑ROS and ↓Akt In vitro Prostate cancer ↓the development of G1 to S phase LN- (Kaseb et al., 2007) CaP prostate cancer cells ↓androgen receptors, ↓E2F-1, ↓E2F- 1-regulated proteins such as cyclin A, Cdk-2, and Cdk-4 In vitro p53-null MG63 and p53-mutant ↑G2/M arrest (Roepke et al., 2007) MNNG/HOS (human osteosar- ↑p21WAF1 coma cells ) Efficacy of some plants and herbs in cancer therapy for humans and animals 321 Table 3 – contd. 1 2 3 4 5 In vitro p53-null myeloblastic leukemia ↑caspases-8,3,9, and ↑Bax/Bcl-2 ratio (El-Mahdy et al., 2005) HL-60 cells In vitro Human colorectal cancer cells G0/G1 arrest (Gali-Muhtasib et al., (HCT-116) ↑p53 2004) ↑Bax/Bcl-2 ratio In vitro Mouse papilloma carcinoma cells G0/G1 arrest, ↑p16, ↓cyclin D1 (Gali-Muhtasib et al., (SP-1) G2/M arrest, ↑p53, ↓cyclin B 2008) In vitro Colorectal cancer cells (p53-null ↑apoptosis (Gali-Muhtasib et al., HCT-116 cells) 2008) In vitro U266 multiple myeloma cells ↓STAT3 (Li et al., 2010) ↓cyclin D1, ↓Bcl-2, ↓Bcl-xl, and ↓sur- vivin ↓Src, ↓Akt and ↓Jak2 ↓VEGF In vitro FG/COLO357 (pancreatic cancer ↓migration of cancer cells (Torres et al., 2010) cells) ↓Mucin-4, and ↑JNK In vitro KBM-5 human myeloid cells ↓NF-kB-regulated gene products and (Sethi et al., 2008) ↓NF-kB activation, ↓TNFα-induced expression of ↓VEGF, ↓expression of MMP-9, ↓transcripts of XIAP, Bcl-xl, Bcl-2, IAP2, IAP1, and survivin In vitro M059J and M059K glioblastoma ↓telomerase and caused telomere attrition (Gurung et al., 2010) cells In vitro DLD-1 human colon cancer cells ↓phosphorylation of ERK and JNK (El-Najjar et al., 2010) ↑activation of caspase-3, and -7 and ↑generation of ROS In vitro SiHa human cervical squamous ↓expression of Bcl-2, ↑expression of p53; (Ng et al., 2011) carcinoma cells ↑Sub-G1 arrest In vitro MCF-7 cells ↓mRNA expression of CYP 1A1 and (Motaghed, et al., 2014) UGT1A8 (Kundu et al., 2014) (Rajput et al., 2013) In vitro HaCaT cells ↑Protein and mRNA expression of HO-1 (Kundu et al., 2014) In vitro Breast cancer cells (T47D and ↓expression of cyclin D1, E, Bcl-2 and (Rajput et al., 2013) MDA-MB-468) survivin ↑expression of p27; ↑Bax, ↑cytoplasmic cytochrome c; ↑caspase 3 Induced G1 phase cell cycle arrest ↓phosphorylation of GSK3, PTEN, Akt, and PDK1 In vitro PBD of Plk1; HeLa Induction of mitotic arrest, ↓Polo box (Reindl et al., 2008) domain function, Plk1 activity. meddling with Plk1 localization to centrosomes In vitro Multiple myeloma cells phosphorylation of STAT3, ↓expression (El-Far et al., 2016) of Bcl-2 and Bcl-xl. ↓F-actin polymerization In vitro HeLa cells ↓expression of NF-B. (Sakalar et al., 2013) ↑pro-apoptotic genes, CASP1, BIK, FASL In vitro A431 and Hep2 cells ↓phosphorylation of JNK and Akt (Das et al., 2012) ↑Sub-G1 arrest and TUNNEL positivity; ↑cytochrome c,↑Bax/Bcl-2 ratio, and activation of caspases In vitro Human neuroblastoma cells ↓XIAP and VEGF proteins, ↓expres- (Paramasivam et al., sion of XIAP ↓mitochondrial membrane 2012) potential. ↑Bax/Bcl-2 ratio; ↑activation of caspase-9 and -3. In vitro Glioblastoma cells ↓Secretion and activity of MMP-9 and -2, (Kolli-Bouhafs et al., ↓phosphorylation of ERK and↓FAK. 2012) 322 M.E. Abd El-Hack et al. Table 3 – contd. 1 2 3 4 5 In vitro Pancreatic ductal adenocarcinoma ↓histone deacetylase (HDAC) activity, (Chehl et al., 2009) (PDA) cells PDA, MCP-1, ↓Cox-2, ↓TNF-alpha, and ↓interleukin (IL)-1beta. ↑histone hyperacetylation, ↑p21 WAF1 expression. In vitro Human HL-60 leukemia, 518A2 ↑ROS and ↑apoptosis related to DNA (Effenberger et al., melanoma, multidrug-resistant tearing, ↓MMP and 2010) KB-V1/Vbl cervix, and MCF-7/ Topo breast carcinomas, non- malignant human foreskin fibroblasts In vitro and in Gastric cancer cells ↓Tumor growth in xenograft mice and (Lei et al., 2012) vivo ↑5-FU-induced apoptosis. In vitro and in SaOS-2 cells and mice ↓Expression of CD34, NF-B, and VEGF. (Peng et al., 2013) vivo Lipid fraction and aqueous In vitro Human MCF-7 breast cancer cells Cytotoxic to MCF-7 cells at low concen- Mahmoud and (Torchi- extract trations lin, 2012) ↑Antitumor activity of doxorubicin Hydroalcoholic extract of In vitro Human renal adenocarcinoma ↓Cell viability of ACHN. (Shahraki et al., 2015) N. sativa (ACHN) and normal renal epithe- Apoptotic effect of total extract in ACHN lial (GP-293 cell lines) cells compared with the GP-293 cells Hydroalcoholic extract In vitro ACHN cell (normal renal epithe- ↓ACHN cell viability and no cytotoxicity (Shahraki et al., 2016) (30% distilled water and lial). in GP-293 cells 70% alcohol) Seeds of N. sativa in In vitro Hepatocarcinogenesis ↓liver cancer in male Wistar rats (Iddamaldeniya et al., combination with Smilax ↓number of cells/cm2 of the positive foci 2003) glabra rhizome and ↓DEN-induced GST-P positive foci Hemidesmus indicus root N. sativa plant extract In vitro Human hepatoma HepG2 cells ↓DNA synthesis (Thabrew et al., 2005) induced cell apoptosis and/or necrosis N. sativa extracts In vitro Human breast cancer MDA- ↓the proliferation of human breast cancer (Dilshad et al., 2012) MB-231 cell cells through the induction of apoptosis Aqueous and alcohol In vitro MCF-7 breast cancer cells ↓the potency and survival (Farah and Begum, extracts 2003) A crude gum, a fixed oil In vitro MDR (human tumor cell lines) Cytotoxic effect through ↑cell accumula- (Worthen et al., 1998) and two purified compo - tion nents of N. sativa seed, TQ, and dithymoquinone N. sativa seed oil (NSO) In vivo Colon carcinogenesis in Fischer ↓cell proliferation in the colonic mucosa (Salim and Fukushima, 344 rats 2003) In vitro HEK293, MCF-7, A-549 and ↓percentage cell viability of MCF-7, (Al-Oqail et al., 2017) HepG2 cell lines A-549, and HepG2 cells, ↓GSH, ↓MMP, ↓bcl-2 ↑ROS, LPO , ↑p53, caspase-3, 9, and bax. In vitro Human fibro- ↓u-PA (urokinase-type plasminogen (Awad, 2005) sarcoma cell line, HT1080 activator) ↓PAI-1 (plasminogen activator inhibitor type 1) ↓t-PA (type plasminogen activator) In vitro Human monocyte and mac- ↓cell growth and differentiation in mono- (Mat et al., 2011) rophages cyte and monocyte-derived macrophage An experiment on male Wistar rats found that the dithymoquinone and TQ of N. sativa seed produced mixture containing seeds of Smilax glabra rhizome, N. a cytotoxic effect through increased cell accumulation sativa, and Hemidesmus indicus root has repressed hepa- in parental and multi-drug resistant (MDR) human tu- tocarcinogenesis (Iddamaldeniya et al., 2003). Another mor cell lines (Worthen et al., 1998). Finally, numerous mixture containing crude gum (as a fixed oil) and both in vivo and in vitro data promoted the high therapeutic Efficacy of some plants and herbs in cancer therapy for humans and animals 323 value of N. sativa seed oil in the induction of apoptosis and 13 ug/mL and IC50 values extending between 5 and repression of cell proliferation in the colonic mucosa and 7 ug/mL (Taleb et al., 2014). Furthermore, the es- (Salim and Fukushima, 2003), HEK293, A-549, HepG2, sential oil of C. libani was also cytotoxic alongside and MCF-7 cell lines (Al-Oqail et al., 2017), human drug-sensitive CCRF/CEM acute lymphoblastic leu- fibrosarcoma cell line, HT1080 (Awad, 2005), and hu- kemia cells and their multidrug-resistant P-glycopro- man monocyte and macrophages (Mat et al., 2011). tein-expressing subline, CEM/ADR5000 (Saab et al., 2012). cedar (Cedrus libani) Cedrus libani is one of the four Cedrus species costus ( Costus speciosus) (Pinaceae). C. libani and the other three naturally exist Costus speciosus (Family: Costaceae) is an impor- in the Mediterranean Sea area: C. libani in Turkey, Leb- tant medicinal plant known as spiral ginger. C. speciosus anon, and Syria, C. atlantica in Morocco and Algeria, is broadly applied as a folk medicine for treating various and C. deodara in the Himalaya Mountains, while C. complaints (Pawar and Pawar, 2014). It is widespread in brevifolia, on Cyprus Island (Abd El-Hack et al., 2016, tropical and subtropical regions of Africa, the Americas, 2018, 2020, 2021). It is a perpetual tree with a thick and Asia, particularly in India, Indonesia, Sri Lanka, and branch extended horizontally, a short and wide trunk, Malaysia (Specht and Stevenson, 2006; El-Far et al., and a broad corona with a pyramidal shape. The length 2016). of this plant reaches 20–40 m and up to 3 m in diameter, The rhizomes of the plant are characterized as bit- with glaucous blue-green leaves (8–25 mm), with a life ter and astringent. Pharmacological studies showed as long as 1500–2000 years (Kurt et al., 2008). C. libani that the rhizomes and root parts of C. speciosus pos- has been reported to have various biological activities; sess antioxidant, anti-stress, antibacterial, antifungal, tar is obtained from its steam wood and resinous root, and anti-inflammatory properties (Selim and Al Jaouni, and it generally possesses antibacterial and insecticidal 2015). Otherwise, the leaf extract of C. speciosus was activities (Saeed et al., 2017, 2018; Abdel-Moneim et shown to have probable in vitro anticancer action con- al., 2020; Reddy et al., 2016). Other studies revealed cerning hepatic cancer (El-Far et al., 2016). Addition- its antiulcerogenic properties (Yeşilada et al., 1999). ally, C. speciosus is a significant source of many mol- Anticancer activities of C. lebani are summarized in ecules possessing different pharmacological incomes, Table 4. such as saponins, B-sitosterol; diosgenin, dioscin, It was reported by Saab et al. (2011) that C. libani and prosapogenins A and B of dioscin, γ-tocopherol, ethanol and chloroform seed extract brought erythroid among others. Moreover, the major compound of differentiation and growth restraint in K562 cells (hu- C. speciosus oil was found to be costunolide (Selim man chronic myelogenous leukemia cells) with IC of and Al Jaouni, 2015). The therapeutic properties of C. 40.57 µg/mL and 69.20 µg/mL respectively. The speciosus extracts may be accredited by using vari- essential oil of C. libani also persuaded erythroid differ- ous ingredients such as flavonoids, alkaloids, sesquit- entiation and growth inhibition in K562 cells with IC of erpenes, and saponins. All conceivable up-regulation 23.38 µg/mL (Saab et al., 2012). of cellular apoptotic mediators as caspases, p21, p27, The 2-himchalene-7-ol (2HC7), a white crystal- p53, reactive oxygen species generation and others, line solid (125 mg, 0.3%), was isolated from the oil of characteristic of the anticancer properties of C. spe- C. libani by Taleb et al. (2014). The isolated 2HC was ciosus toward the down-expression of the anti-apop- then confirmed alongside colon (Caco-2) or brain (SF) totic mediators (El-Far et al., 2016). As seen in Ta- cancer cells at different levels extending between 1 and ble 5, we summarized the potential anticancer activities of 25 ug/mL. Results showed a noteworthy anti-prolif- C. speciosus according to the in vivo and in vitro ex- erative property with IC99 values ranging between 11 periments. Table 4. Anticancer activities of C. lebani Mechanisms Extract/active ingredient Study type Cancer cell type References of action Ethanol and chloroform seed extract In vitro in K562 cells (human chronic myelogenous leukemia ↓Cell growth (Saab et al., 2011) cells) Essential oil In vitro in K562 cells (human chronic myelogenous leukemia ↓Cell growth (Saab et al., 2012) cells) Essential oil In vitro CCRF/CEM acute lymphoblastic leukemia cells and ↓Cytotoxicity (Saab et al., 2012) CEM/ADR5000 (multidrug-resistant P-glycoprotein- effect expressing subline) 2-himachalene-7-ol In vitro SF (brain cancer cells) and Caco-2 (colon cancer cells) ↓Proliferation (Taleb et al., 2014) 324 M.E. Abd El-Hack et al. Diosgenin and dioscin have been reported to have 15–20 ft with several spreading branches and a trunk more anticancer activity and are considered of great inter- than 7 ft in diameter (Chawla et al., 2012). The utmost est to the pharmaceutical industry (Selim and Al Jaouni, imperative species of Ficus are F. racemose, F. elastica, 2016). Indeed, diosgenin induces apoptosis and inhibits F. bengalensis, and F. carica. Almost all plant portions, such cell viability in different cancerous cells (HepG2, HL-60, as leaves, fruits, bark, shoots, latex and seeds, are medici- and MCF-7 and Saos-2) (Selim and Al Jaouni, 2015). Si nal. The Ficus is a beneficial health plant applied widely in milarly, the anticancer activity via apoptosis induc- different industrial and pharmaceutical uses. This feature is tion and cell viability inhibition was described for Cos- due to its richness in vitamins, micro and macro minerals, tunolide in MDA-MB-231 and MCF-7 cells, shown water, fats and various phytochemicals such as flavonoids, in in vivo and in silico assays (Pitchai et al., 2014; Roy phenol, terpenoids, and other sources of calcium and fiber and Manikkam, 2015). On the other hand, dioscin – a (Caliskan, 2015). Hence, the hepatoprotective, antioxidant, derivative from diosgenin – was described to induce antidiabetic, anticancer, antiplatelet, anthelmintic, diuretic, apoptosis in HeLa cells through cyclooxygenase activ- hypolipidemia, and immunity activities of Ficus have been ity in osteosarcoma cells (Selim and Al Jaouni, 2016). studied by various investigators (Singh et al., 2016). Methanol and hexane extracts of C. speciosus leaves Several studies have reported the anticancer activi- were reported to have in vitro anti-proliferative effects on ties of ficus (Table 6). The constituents of ficus comprise a HepG2, WI-38, and THP-1 cells by inhibiting cell pro- combination of 6-O-acyl-beta-D-glucosyl-beta-sitosterols, liferation (Selim and Al Jaouni, 2015; Singh et al., 2016). the acyl moiety being mainly linoleyl and palmitoyl with The possible mechanisms of action of the black seed, Ce- minor amounts of oleyl and stearyl, displayed powerful drus libani, and Costus speciosus are illustrated in Figure 2. cytotoxicity properties on various cell line cancer cells (Rubnov et al., 2001). The F. carica fruits and leaves la- ficus (Ficus carica) tex also showed antiradical activity and antiproliferative Ficus (Ficus carica) is one of the copious kinds of me- activity against A375 (human melanoma cell line) after ex- dicinal plants comprised of about 800 species of shrubs, posing to irradiation at a specific UVA at minimum IC50 woody plants and trees mostly found in tropical and sub- values (Menichini et al., 2012). The anti-proliferative ac- tropical regions worldwide (Herre et al., 2008). Ficus rep- tion of F. carica latex and F. carica latex-temozolomide resents one of the most common traditional Mediterranean mixture was examined in several cell lines, such as U-87 plants in the Moraceae family. F. carica tree normally has MG, T98G, and U-138 MG glioblastoma. Figure 2. The possible mechanisms of action of black seed, Cedrus libani and Costus speciosus Table 6. Anticancer activities of Ficus Study Mechanisms Extract/active ingredient Cancer cell type References type of action 6-O-acyl-beta-D-glucosyl-beta-Sitosterols In vitro Lymphoma cell (Raji Burkitt B), DU-145 prostate Not reported (Rubnov et al., 2001) cancer and MCF-7 cells, Burkitt B cell lymphoma (DG-75), Jurkat T-cell leukemia Latex-temozolomide mixture In vitro U-138 MG, T98G, and U-87 MG glioblastoma Cell death (Tezcan et al., 2015) Leaves, bark and wood extracts In vitro Human melanoma ↓proliferation (Conforti et al., 2012) Bergapten and psoralen from F. carica leaves In vitro Triple-negative breast cancer (MDA-MB-231 cells) Not reported (Zhang et al., 2018) Ficutirucins A-I but ficutirucins A, B, C, F, G In vitro MCF-7, HepG-2, and U2OS ↓Cytotoxicity (Jing et al., 2015) and I possessed anticancer effects effect Efficacy of some plants and herbs in cancer therapy for humans and animals 325 F. carica latex administration produced substantial 2013). Both rodent and human studies have reported that cell death in glioblastoma multiforme cells with various garlic or its preparations can suppress the development of responses to F. carica latex-temozolomide mixture (Tez- chemically encouraged tumors in hepatic tissues (Kweon can et al., 2015). Khodarahmi et al. (2011) also affirmed et al., 2003), esophagus (Chen et al., 2009), stomach (Tu- the anticancer properties of F. carica latex on human rati et al., 2015), colorectum (Galeone et al., 2006), blad- cancer cells using HeLa cell line in vitro using the MTT der (Turati et al., 2015), and prostate (Hsing et al., 2002). assay. Leaves were revealed to have repression of peroxi- The possible mechanisms of action of fig and garlic are dation and the highest anti-radical action with IC values illustrated in Figure 3. of 1.48 and 64 μg/ml, respectively. Conforti et al. (2012) found that the leaves had the maximum anti-proliferative ginger (Zingiber officinale ) action with an IC value of 3.92 μg/mL. Psoralen and Ginger (Zingiber officinale ) is also a very prevalent bergapten are the dominant active molecules in F. carica plant that belongs to the family Zingiberaceae. It origi- leaves with general anticancer action on MDA-MB-231 nated in South-East Asia and its rhizome is applied in (triple-negative breast cancer cells), representing that numerous countries as a spice and food flavor (Park and these two components might show imperative function Pezzuto, 2002). Several health-promoting perspectives in anticancer activities of F. carica leaves (Zhang et al., of ginger are accredited to its rich polyphenols, such as 2018). Likewise, the anticancer efficiency of ethanolic gingerols (mainly in the fresh rhizome) and shogaols (de- extract of pulverized fruit of F. carica was examined on hydrated gingerol derivatives in dried rhizome) (Jolad et breast cancer cell lines MCF-7. The extract presented al., 2004; Jiang et al., 2006). robust anti-tumor actions at 85.5 and 89% suppression Using ginger can be considered safe, although fur- after 24 and 48 hours, respectively, at levels of 1000 μg/ ther understanding of its mechanisms of action is needed. mL, while the low level showed the proportion inhibition Ginger has several therapeutic uses, including degenera- was 76, 80.5 and 82.5% at 24, 48, and 72 hours, respec- tive and cardiovascular syndromes, vomiting, digestive tively (Jasmine et al., 2015). Jing et al. (2015) examined health, diabetes mellitus, and even cancerogenic (Jiang et the cytotoxic activities of many molecules isolated from al., 2006; Patel et al., 2007). It also possesses anti-inflam - F. carica fruits, ficutirucins A-I, and these molecules ex- matory, anti-oxidative properties and antimicrobial po- hibited moderate cytotoxic actions with IC values of tential against gram-positive and gram-negative bacteria 11.67–45.61 μM alongside many cancer cell lines in hu- (Jiang et al., 2006; Patel et al., 2007; Singh et al., 2008). man such as U2OS, MCF-7, and HepG-2. Evidence from both in vivo and in vitro studies (Table 8) recommends that ginger and its active components con- garlic ( Allium sativum) strain the development of several cancer types, includ- Garlic (Allium sativum L.), originally from Asia, is ing breast, renal, cervical, colon, gastric, oral, pancreatic, a bulbous plant that can easily grow in mild climates. prostate, hepatic, and brain cancer (Tuntiwechapikul et Garlic has played an important dietary role as a spice al., 2010; Kim et al., 2014; Wu et al., 2015). Shogaol sup- and food additive (Eja et al., 2007). Garlic can be con- presses the growth and brings apoptosis of non-small cell sumed in the form of raw garlic, raw garlic homogen- lung cancer cells (Kim et al., 2014; Wu et al., 2015) and ate, an aqueous extract of garlic, garlic oil, crushed or enhances gemcitabine properties in human pancreatic chopped garlic and aged garlic extract. The main com- cancer, such as BxPC-3 and PANC-1 (Gan et al., 2011). pound present in intact garlic is alliin. Alliinase enzyme produces allicin from alliin when garlic is chopped or indigo (Indigofera tinctoria) crushed. Also, other sulfur compounds such as diallyl Indigofera tinctoria belongs to the family Fabaceae disulphide, S-allylcysteine, and diallyl trisulfide contrib- and is a widely distributed one- to two-meter height ute to some of the garlic effects (Lanzotti et al., 2012). shrub found in several regions, Southeast Asia and the Several medicinal and therapeutic effects of garlic or gar- Indian subcontinent, Africa, and America (especially in lic preparations have been reported. These effects range tropical areas). The alcoholic extract of the leaves has from improving detoxification of foreign compounds and an antihepatotoxic influence on carbon-tetrachloride and hepatoprotection or cardiovascular protection to anti- D-galactosamine-triggered hepatic damage (Sreepriya oxidant effect, antimicrobial effect, or even suppressing et al., 2001). Indigtone, an active constituent located in the risks of cancer (Colín-González et al., 2012). leaves has hepatoprotective activity (Singh et al., 2001). Table 7 summarizes studies of the anticancer activities Moreover, I. tinctoria influences chronic myelogenous of garlic. leukemia (Steriti, 2002). Indirubin showed noticeable re- The cancer-preventive effects of garlic or its prepa- pression of Walker carcinoma and Lewis lung carcinoma, rations that contain allylsulfide derivatives have been signifying that I. tinctoria has considerable antineoplas- extensively reported. Some studies on garlic anticancer tic activity (Han, 1994). Another type of indigo called action have shown that it can be established via the mod- Polygonum tinctorium belongs to the family Polygonace- ulation of several molecular mechanisms responsible for ae. In its leaves, P. tinctorium stores large quantities of carcinogenesis, including DNA adduct formation, mu- a colorless glycoside, indican (indoxyl beta-D-glucoside) tagenesis, cell proliferation and angiogenesis (Capasso, (Selvius et al., 2011). 326 M.E. Abd El-Hack et al. Table 7. Anticancer activities of garlic Extract/active ingredient Study type Cancer cell type Mechanisms of action References Garlic products In vivo Prostate cancer ↓prostate cancer risk. (Hsing et al., 2002) In vitro Fresh garlic In vivo Prostate cancer ↓ratio of prostate cancer by 30-50%. (Hsing et al., 2002) Garlic products Stomach cancer ↓Death ratio by 10-folds (Setiawan et al., 2005) In vivo ↓risk of stomach cancer. Fresh garlic In vivo Gastric cancer ↓nitrate-reducing bacteria and ↓nitrite formation. (Turati et al., 2015) Raw garlic Esophageal cancer ↓the risks of esophageal cancer. (Galeone et al., 2006; In vitro Chen et al., 2009) Garlic products In vitro Pancreatic cancer ↓risk of pancreatic cancer due to garlic use. (Chan, 2005) Garlic products In vitro Colorectal cancer ↓risk of colorectal cancer (Galeone et al., 2006) Figure 3. The possible mechanisms of action of fig and garlic Table 8. Anticancer activities of ginger Extract/active ingredient Study type Cancer cell type Mechanisms of action References Shogaols In vivo Lung cancer ↓tumorigenesis, ↓NF-B activation, ↓COX-2, and ↓iNOS, (Kim et al., 2014) ↓development and apoptosis biomarkers of cancer cells via Akt1/2 pathway Shogaols In vitro Pancreatic cancer ↓Bcl-2, MMP-9, cIAP-1, cyclinD1, surviving, XIAP, and (Gan et al., 2011) Bcl-2. ↓Antitumor activity, ↓TLR4/NF- B signaling ↑PANC-1 and BxPC-3 ↓TLR4/NF- B, ↓formation of cancer cell colony. Ethyl acetate In vitro Lung cancer ↑cell death, ↓hTERT (human telomerase reverse tran- (Tuntiwechapikul (A549) scriptase) and c-Myc. et al., 2010) Young Zingiber officinale and In vitro MCF-7, and PC- ↑cytotoxic effect against MCF-7, PC-3, and A-549 cancer (Zu et al., 2010) its essential oil 3, A-549 cells; ↓risk of hepatic cancers Ethanol extract In vitro Colon cancer ↓mTOR and Wnt/ catenin signaling pathways, ↑apoptosis in (Abdullah et al., HT29 cells. 2010) ↓S-phase population in HT29 and HCT-116 cells. Efficacy of some plants and herbs in cancer therapy for humans and animals 327 The indigo plant has been used in medicine in Japan, ence of leaf extract on NCI-H69 (lung cancer cell line) China, and Korea for over a thousand years (Cooksey, was found to be eminent by augmenting the level of 2012; Heo et al., 2012). The main bioactive substances leaf extract. in the indigo plant are mostly flavonoids, polyphenols, Heo et al. (2014) investigated the cytotoxic influ- tannins, and flavonols (Heo et al., 2013). In addition, this ences of the ethanol, water, and methanol extracts of plant’s most beneficial active principles are indirubin, in- leaves, flowers, seeds, and stems of indigo on HEK 293 digo, kaempferol, and tryptanthrin (Cooksey, 2012). (human renal cell line) and suppressor influences on the Kameswaran and Ramanibai (2008) explored indigo proliferation of MCF-7 (breast carcinoma cells), HeLa aerial parts’ potential anticancer activity (against human (cervical carcinoma cells), HCT-116 (colon cancer cell), non-small cell lung cancer cells A-549). Interestingly, fla- Hep3B (liver carcinoma cells), SNU-1066 (laryngeal vonoid molecules isolated from the ethanolic extract of cancer cell) and SNU-601 (gastric cancer cell). The high- indigo considerably repressed the proliferation of A-549 est concentration of total polyphenols was detected in cells. Flow cytometric analysis revealed that methanolic methanol extracts of flowers and leaves. However, the extract of I. tinctoria stopped cell cycle development in methanol extract of seeds, flowers and leaves has the G0/G1 stage and boosted A-549 cell apoptosis. The au- highest proportion of flavonoids. The maximum antioxi - thors suggested that flavonoid screening of methanolic dant capacities were also detected in methanolic extracts extract of I. tinctoria action might contribute to its overall of leaves and flowers. The highest relation between the chemo-preventive impacts alongside lung cancer. They survival rates and the antioxidant abilities was in metha- might probably be measured for upcoming therapeutic nol extracts of leaves on HeLa cells (Heo et al., 2014). uses. So, in vitro studies showed that the indigo extracts were Oral administration of methanolic fraction of detected to be efficient in constraining the development I. tinctoria at levels 100 and 200 mg/kg markedly low- of cancer cells (Table 9). ered the increased level of uronic acid and hexosamine The use of naturally accessible fuels for nanoparti- content compared to vehicle-treated control one. The in cle solution combustion synthesis (SCS) has increased. vitro cytotoxic action of methanolic extraction of I. tinc- Many studies reported that biofuels have harmless en- toria on melanoma cells (B16F10) was recorded at 24.8 vironmental effects, but their tactical recompenses for µg/ml at IC50. Renukadevi and Sultana (2011) studied the synthesis of NPs have not been fully investigated. the cytotoxic, antioxidant and antibacterial activity of Prashanth et al. (2018) studied the usage of plant ex- the leaf extract of I. tinctoria. The cytotoxic activity of tracts as biofuels for the SCS of zinc oxide nanoparti- leaf extract was determined on a lung cancer cell line. cles (ZnNPs). The authors carried out the combustion The phytochemical examination found several active synthesis of ZnNPs by using aqueous and lactose leaf molecules like saponins, flavonoids, steroidal terpenes, extracts of Indigofera tinctoria, Melia azedarach, Abu- tannins, anthraquinone and phenols. The robust anti- tilon indicum as biofuels. A comparative analysis has oxidant activity of the indigo extract was detected at been conducted to comprehend the benefits of using –l 250 µg mL with an IC value of 51.66, which is more plant extracts over a biochemical as a combustion fuel than that of standard ascorbic acid. The cytotoxic influ- for synthesizing ZnNPs. Table 9. Anticancer activities of indigo Extract/active ingredient Study type Cancer cell type Mechanisms of action References The methanolic extract of aerial In vitro Human non-small cell Flavonoid fraction of methanolic extract (Kameswaran and Ra- parts of the plant Lung cancer cells a-549. of I. tinctoria prohibited cell cycle de- manibai, 2008) velopment in GO/G 1 Phase and induced a-549 cell apoptosis. ZnNPs synthesized using lactose In vitro DU-145 and Calu-6 cancer The machinery of apoptosis (Prashanth et al., 2018) and aqueous leaf extracts cells in cancer cells due to ZnNPs still not be- ing explored. I. tinctoria leaf extract and the In vitro Lung cancer cell line A549 Induce reactive oxygen species (Vijayan et al., 2018) nanoparticles of gold and silver by nanoparticles. It reasons reparations to the cellular con- stituent and leads to the cell death Water, methanol and ethanol In vitro Hek 293, HEP3b, MCF-7 Flavonoids and polyphenols in extracts of (Heo et al., 2014) extracts of flowers, leaves, stems, HCT-116, Hela, snu-1066, various parts of indigo. and seeds from indigo and snu-601. (P. tinctorium) Methanol and ethyl acetate from In vitro Calu-6 (human cancer cell Tryptanthrin and indirubin, both com- (Jang et al., 2012) the indigo powder, seeds, or the lines) and SNU-601 (human pounds originating from indican in the prolipid. gastric carcinoma) leaves of P. tinctorium are responsible for many of the biological activities of this Plant. 328 M.E. Abd El-Hack et al. pomegranate (Punica granatum) Moreover, the authors conducted antiproliferative eval- Pomegranate is a long-lived and drought-tolerant uation against Calu-6 and DU-145 cancer cells and detected small tree. It is mainly found throughout the Mediter- the higher anticancer action of ZnNPs ready utilization ranean, Iran, India, China, and the USA (Ercisli et al., biofuels. The biocompatibility of ZnNPs at lower concen- 2011). The pomegranate consists of different compart- trations was detected by blood hemolysis. Further studies ments: seed, juice, peel, and leaf. The chemical composi- would be needed to validate the potential benefits of natural- tion of the fruits depends on several factors, including ly offered fuel usage in SCS. Vijayan et al. (2018) reported the growing region, climate, cultivation practice, and the innovation of novel metal nanoparticles, explicitly gold storage conditions (Fadavi et al., 2005). The peel con- (AgNPs) and silver (AuNPs), from their salt by using leaf tains important bioactive constituents like flavonoids, extract of I. tinctoria. This leaf extract acts as a stabilizing phenolics, proanthocyanidins, ellagitannins, and other and reducing mediator for the creation of nanoparticles. The significant minerals. The edible part of the pomegran - antiproliferative influence of I. tinctoria leaf extract and the ate fruit is rich in several bioactive molecules such as nanoparticles were investigated in A549 (lung cancer cell). flavonoids and phenolics, mainly anthocyanins (Viuda- It was detected that the elevating concentration reduces cell Martos et al., 2010) that prevent lipid peroxidation of viability, and the pure leaf extract has a less toxic influence cells. Pomegranate seeds contain estrogenic compounds on cancer cells than nanoparticles. Studies have shown that like estrone and estradiol (Kim and Choi, 2009). The the IC value of AgNPs, and AuNPs (biogenic synthesis) by seed cover of the fruit contains delphinidin-3,5-diglu- I. tinctoria leaf extract are 56.62±0.86l g/ml, 59.33±0.57l g/ coside, the primary anthocyanin in pomegranate juice ml and 71.92±0.76l g/ml, respectively. Moreover, the syn- (Elfalleh et al., 2012). Pomegranate juice, pomegranate thesized metal nanoparticles showed high antimicrobial ac- extracts, and seed oil have interesting pharmacological tions. activities. Extracts of all parts of the pomegranate fruit have numerous biomedical applications and therapeutic onion (Allium cepa ) properties ranging from being utilized as a medication Onion, a biennial plant, generally adapts to temperate for dysentery, diarrhea, hemorrhage, acidosis, helminth environments with low water supplies. It is thought to infection, microbial infections, and respiratory patholo- have originated in central Asia (Zeng et al., 2015). On- gies (Kim and Choi, 2009) or even targeting a variety ion can be used in fresh, raw and processed forms. Be- of ailments including cardiovascular syndromes, Alz- sides its culinary uses, it is considered a good medicinal heimer’s disease, male infertility, aging, diabetes, and and therapeutic compound for many diseases (Nuutila AIDS or even cancer (Lansky and Newman, 2007; Ju- et al., 2003; Vidyavati et al., 2010). Onions are rich in renka, 2008). two bioactive ingredients, including flavonoids, such as Recently, pomegranates have been reported for their anthocyanins and flavanols, such as quercetin, and the wide range of anti-cancer properties, especially in breast sulfur-containing compounds (alk(en)yl cysteine sulph- and prostate cancers. Fermented pomegranate juice has oxides (ACSOs)) (Alagawany et al., 2014, 2016; Dosoky doubled the pomegranate extracts’ effect in constraining et al., 2021). The numerous reported health properties of the development of MCF-7 (breast cancer cells) via stim- onions in vitro and in vivo are due to their antioxidant, ulation of apoptosis (Mehta and Lansky, 2004; Jeune et hypocholesterolemic, hypoglycemic, and thrombolytic al., 2005; Bassiri-Jahromi, 2018). Pomegranate fruit has or even anticarcinogenic effects (Vidyavati et al., 2010). been reported to inhibit cell growth, induce apoptosis of Onions may have anticarcinogenic properties, as re- human prostate cancer, and prevent hepatocellular carci- ported in both animal and human trials against a wide noma in humans (Kaplan et al., 2001). Pomegranate ex- range of cancer types, such as esophageal, gastric, colo- tract has antiproliferative activity in non-small cell lung rectal, hepatic, renal, lung, bladder, breast, ovarian, and carcinoma cell lines both in a time- and dose-dependent brain cancer (Fukushima et al., 1997; Hsing et al., 2002; manner (Khan et al., 2008; Husari et al., 2017; Sharma Galeone et al., 2006; Millen et al., 2007). Table 10 shows et al., 2017). the anticancer activities of onion. In breast cancer, the Pomegranate fruit extract can be used in human lung tetrasulfide compound naturally occurring in onion can cancer therapy by inhibiting several signaling pathways inhibit the proliferation of both sensitive and resistant such as mitogen-activated protein kinases (MAPK), human breast carcinoma cells by targeting the enzymes PI3K/Akt, and NFκB (Khan et al., 2007). Pomegranate involved in the cell cycle (Galeone et al., 2006; Millen oil treatments have reduced tumor incidence and numbers et al., 2007). Several reports have concluded that onion in mice (Viuda-Martos et al., 2010; Elfalleh et al., 2012). or onion products can repress the growth of several hu- The bulk of investigations showed that the pomegranate man cancer cell lines, including stomach and colon cells pulp extract exerts anti-skin tumor-encouraging action in (Setiawan et al., 2005; Turati et al., 2015). Also, onion CD-1 mice (Pacheco-Palencia et al., 2008). Additionally, intake has been consistently associated with decreas- pomegranate seed oil supplementation improved the ex- ing the risk of colorectal cancer (Millen et al., 2007). pression of PPARα in the non-tumor mucosa and mean- A study by Hu et al. (1999) has described that dietary ingfully reduced the occurrence of colonic adenocarci- supplementation with onion products is associated with nomas (Kohno et al., 2004). The anticancer activities decreased brain cancer risk. Efficacy of some plants and herbs in cancer therapy for humans and animals 329 of pomegranate were detected by several authors granate can constrain the development of cancer cells (Table 11). In vitro experiments have revealed that pome- such as lymphoid cell line (K562- 4), EJ cell – UBUC granate juice possesses anti-inflammatory effects on the T24, glioma cells (U87MG), and J82 cell (Joseph et al., signaling proteins found in human colon cancer (HT-29 2012; Dahlawi et al., 2013). The possible mechanisms cell line) (Seeram et al., 2005). Several in vitro stud- of action of pomegranate and onion are illustrated in ies have reported potential machinery via which pome- Figure 4. Table 10. Anticancer activities of onion Cancer Extract/active ingredient Study type Mechanisms of action References cell type Onion products - organo- sulphur In vitro Breast ↓risk of breast cancer (Viry et al., 2011) compounds such as tetrasulfides In vivo cancer ↓the proliferation of sensitive and resistant human breast carcinoma cells by targeting the cell division cycle 25 phosphatases, crucial enzymes of the cell cycle Fresh onion In vivo Gastric ↓of nitrate-reducing bacteria and ↓nitrite formation. (Turati et al., 2015) cancer Fresh onion In vivo Prostate ↓risk of prostate cancer (Hsing et al., 2002) cancer Onion products and derivatives In vivo Colorectal ↓risk of colorectal cancer. (Millen et al., 2007) cancer Onion products – quercetin and In vivo Lung ↑anticancer properties as demonstrated in lung cancer (Vijayababu et al., 2006) derivatives cancer Onion – quercetin and luteolin In vivo Skin ↑anticancer properties as demonstrated in skin cancer. (Vijayababu et al., 2006) cancer ↓UVB-induced skin tumorigenesis in SKH-1 hairless mice via ↓PKCε and c-Src kinase activity. Onion products – onion peel – total In vitro Stomach ↓growth of several human cancer cell lines, including (Setiawan et al., 2005; phenolics and flavonoids cancer cells of the stomach and colon Turati et al., 2015) Onion – quercetin and derivatives In vitro Liver ↑anticancer properties as demonstrated in liver cancer (Fukushima et al., 1997) cancer Table 11. Anticancer activities of pomegranate Extract/active ingredient Study type Cancer cell type Mechanisms of action References 1 2 3 4 5 Juice, seed oil, In vitro Breast (MCF-7- MCF- ↓Growth of MCF-7 through ↑apoptosis. (Jeune et al., , 2005; fermented juice In vivo 7aro) ↓Expansion of new blood vessels. Bassiri-Jahromi, 2018) polyphenols, extract Seed oil, fermented juice In vitro Prostate (DU-145, PC-3) Patients with prostate cancer, pomegranate (Seeram et al., 2005) polyphenols, extract, juice has revealed substantial prolongation juice repetition time of prostate precise antigen. Fruit extract In vivo A549 lung carcinoma ↓H1299 cell survival by arresting cell (Khan et al., 2007; In vitro cells cycle progression in G2/M phase. Khan, et al., 2008; ↓HIF-1α and PHH3 expression. Husari et al., 2017; ↓cell proliferation, ↓pro survival path- Sharma et al., 2017) ways, ↓tumor growth in the nude mice, ↓formation of lung nodules. Seed oil, fruit extract, pulp extract In vivo Skin ↑interleukin 1 (IL-1) and IL-1 beta from the(Hora et al., 2003; cells in the mice and human’s macrophag- Afaq et al., 2005; In vitro es. ↑macrophages. Pomegranate pulp Pacheco-Palencia et extract contains anti-skin tumor promoting al., 2008) activity in CD-1 mouse by ↓biomarkers of tetra decanoyl phorbol 13-acetate (TPA)- induced tumor promotion. Seed-oil, juice In vivo Colon ↑PPARγ (Kohno et al., 2004; In vitro Pomegranate seed oil can↓azoxymethane- Adams et al., 2006) induced colon carcinogenesis. Pomegranate juice, total pomegran- In vitro Colorectal ↓NF-kB response element, and PJ also (Seeram et al., 2005; ate ellagitannins; punicalagin, ellagic Cancer (HT-29, HCT- ↓AKT stimulated by TNF-α. Adams et al., 2006) acid, pomegranate tannin extract 116, Punicalagin, EA, TPT and PJ SW620-HT-29) ↑apoptosis, PJ, TPT and punicalagin ↓NF- α mediated COX-2 protein expression 330 M.E. Abd El-Hack et al. Table 11 – cont. 1 2 3 4 5 P. granatum peels extract- In vitro Leukemia (K562- 4 ↓development of K562 cell line through (Joseph et al., 2012; pomegranate juice, polyphenols lymphoid cell line) cell cycle arrest at G2/M phase, Dahlawi et al., 2013) ↑apoptosis. ↓cellular proliferation Pomegranate extract, Pomegran- In vitro Hepatocellular carci- ↓Lipid and protein oxidation in hepatic (Kaplan et al., 2001) ate juice, bioactive components, noma tissues. resveratrol Prevention of hepatocellular ↓cell proliferation, control cell cycle development, and ↑apoptosis in rats. Punicalagin as a polyphenol isolated In vitro Glioblastoma (U87MG ↓U87MG cell viability (Wang et al., 2013) from P. granatum glioma cells) ↑Apoptosis, ↑AMPK/p27, ↑caspase-3 and 9, ADP-ribose ↑autophagy cell death via microtubule- associated protein light chain 3 II, LC3-II breakage. Pomegranate extract, pomegranate In vitro Bladder cancer (EJ cell – ↓bladder cancer cell EJ proliferation via (Zhou et al., 2015) polyphenols UBUC T24 and J82 cell) p53/miR-34a axis, ↓mitochondrial image pathway ↑ER oxidative stress. Figure 4. The possible mechanisms of action of pomegranate and onion Quince (Cydonia oblonga) firm fruit flesh (Pacifico et al., 2012). Silva and Hussain Quince (Cydonia oblonga) is the only species in the (2017) conducted many investigations on C. oblonga genus Cydonia, which falls into the Pomoideae sub- Miller (also known as quince) in the past few years. They family of the Rosaceae along with pear and apple. The proved this plant is a low-cost, safe, and good natural yellow fruit may be apple- or pear-shaped and is con- source of various phenolic components, such as flavonol, sidered a bright yellow, a highly astringent, acidulous, flavone heterosides, and caffeoylquinic acids. Efficacy of some plants and herbs in cancer therapy for humans and animals 331 These compounds could provide the active principles 5-O-caffeoylquinic acid was the major component in the of quince leaf and fruit in the treatment of cough, bronchial methanolic extracts of quince. The authors observed that asthma, and hemorrhoids (Oliveira et al., 2007), cystitis quince fruit and leaf extracts revealed clear anticancer (Sezik et al., 2001), constipation, and as a skin emollient properties. This extract has potential anticancer effects (Pieroni et al., 2004). Quince fruit is considered a pivotal on human colon cancer cells (IC50 = 239.7 (43.2 μg/ dietary source of health-promoting molecules due to its an- mL), while no effects on human kidney cells were ob- ti-ulcerative, antibacterial, anti-inflammatory, anti-obesity, served. The anticancer property of peel and pulp extracts and antioxidant properties (Oliveira et al., 2007; Pacifico et was low in the range of extract levels. Therefore, the first al., 2012). The leaf of quince has also been detected to have study revealed that C. oblonga might be helpful as a can- anti-hemolytic activity (Costa et al., 2009), in addition to its cer chemotherapeutic and/or chemopreventive agent. lipid-lowering activities (Pacifico et al., 2012). Quince fruit Alesiani et al. (2010) isolated 59 active compo- extracts have been mentioned to be efficient in inhibiting nents from Cydonia vulgaris peels and categorized allergic ailments. Conclusively, a lipophilic quince extract them based on their spectroscopic features. Among was detected to have skin moisturizing activities. them, five metabolites have been isolated for the first The antiproliferative influence of pulp and peel time such as 3β-linoleoylurs-12-en-28-oic acid, 3β-(18- polyphenolic extracts from C. oblonga fruit on both non- hydroxylinoleoyl)-28-hydroxyurs-12-ene, tiglic acid tumorigenic cells (HEK 293 and NIH 3T3) and human 1-O-β-d-glucopyranoside, 3β-oleoyl-24-hydroxy-24-ethy- colon adenocarcinoma cells (LS174) was studied by lcholesta-5,28(29)-diene, and 6,9-dihydroxymega-stig- Riahi-Chebbi et al. (2015). The same reported that the masta-5,7-dien-3-one 9-O-β-d-gentiobioside. All the pre- highest anticancer activity, without any toxic effect, was vious compounds were tested for their antioxidant and shown by aqueous acetone peel extract (IC50=5 µg/mL), anticancer activity (especially murine B16-F1 melanoma explicitly on LS174 cells. Phenolic ingredients concen- cells). Pacifico et al. (2012) two complex preparations tration in the pulp fraction is one-third lower than in the were in the focus of the present study, i.e., a lipophilic peel. Regarding the phytochemical screening of aqueous quince wax extract (QWE studied two complex prepa- acetone peel, it was found that 13 phenolic compounds rations of quince phytochemicals, i.e., an aqueous fer- are the major active molecules, including rutin, querce- mented one (QAFE) and a lipophilic quince wax extract tin, (−)-catechin, (+)-catechin, isoquercitrin, hyperin, (QWE). The antiproliferative influence against human cryptochlorogenic acid, chlorogenic acid, p-coumaric HeLa, A549, and HepG2 cell lines was investigated. acid, neochlorogenic acid, kaempferol-3-O-glucoside, QAFE was more active than QWE, but sometimes, its kaempferol and kaempferol-3-O-rutinoside (Fattouch influences seemed to be strongly dependent on exposure et al., 2007). Carvalho et al. (2010) studied the phenol- time. Moreover, lipophilic and hydrophilic quince prepa- ic screening and anticancer activity of quince fruit and rations are non-toxic and have health-promoting activi- leaf alongside colon cancer and human kidney cells. The ties. Table 12. Anticancer activities of quince Extract/active ingredient Study type Cancer cell type Mechanisms of action References Methanolic extract from In vitro Human renal (a-498 and 769-p) Many phenolic compounds showed anticancer (Carvalho et al., leaves and fruits and colon (caco-2) effects, such as flavone heterosides, flavonol 2010) cancer cell lines and hydroxycinnamic acid. Lipophilic quince wax In vitro Human Hepg2, A549, and Hela ↑Apoptosis induction (Pacifico et al., extract and an aqueous cell lines ↑Mitochondrial toxicity 2012) fermented Peel (Peph) and pulp poly- In vitro Human colon adenocarcinoma ↑Apoptosis induction (Riahi-Chebbi et phenolic extracts LS174 cells ↑A cell cycle arrest in the G1/S phase, al., 2015) ↑ROS. ↓NF-κB and VEGF. Cydonia vulgaris peels In vitro Murine B16-F1 melanoma cells Antioxidant activities of 3β-linoleoylurs-12- (Alesiani et al., en-28-oic acid, 3β-(18-hydroxylinoleoyl)- 2010) 28-hydroxyurs-12-ene, tiglic acid 1-O-β-d-glucopyranoside, 3β-oleoyl-24- hydroxy-24-ethylcholesta-5,28(29)-diene, and 6,9-dihydroxymegastigmasta-5,7-dien-3-one 9-O-β-d-gentiobioside 332 M.E. Abd El-Hack et al. The development of substitute cancer-specific drugs by an increase in the production of intracellular reactive is essential to overcome tumor resistance. Riahi-Chebbi oxygen species, caspase-independent apoptosis and a cell et al. (2015) studied the antiproliferative effect of pulp cycle arrest in the G1/S phase. Peel extract suppressed and peel (Peph) polyphenolic extracts from the C. oblon- the pro-survival signaling pathway NFκB. It inhibited ga on both no-tumorigenic cells HEK 293 cells and NIH the expression of numerous cellular indicators that were 3T3 fibroblasts and human colon adenocarcinoma LS174 significant in angiogenesis (vascular endothelial growth cells. The Peph extract revealed the strongest anti-cancer factor, VEGF) and cell cycling (cyclin D1). Interestingly, influence, specifically on LS174 cells. On the other hand, the chemotherapeutical agent 5-FU and the combination each Peph phenolic component alone did not show any peel extract exhibited a synergistic inhibitory influence anti-cancer activity, indicating a synergistic influence of on cell viability. Table 12 shows the anticancer activities phenolic compounds. This influence was accompanied of quince. Table 13. Anticancer activities of thyme Extract/active ingredient Study type Cancer cell type Mechanisms of action References Thyme essential oil In vivo PC-3, A-549 and MCF-7 cancer ↓growth in leukemia cells (Esmaeilbeig et Displayed cytotoxic activity alongside MCF- al., 2015) 7, A-549, and PC-3 cancer cells. Thyme essential oil In vivo Oral cavity squamous cell carci- ↓human head and neck squamous cell carci- (Sertel et al., 2011) noma noma (HNSCC) cell growth. Thyme essential oil In vitro Human ovarian adenocarcinoma ↑anticancer activity. (Ismaili et al., IGR-OV1 cell line 2002) Thyme essential oil In vitro Ovarian cancer in vitro cytotoxic activity against tumor cells (Ait M’barek et (carvacrol) resistant to chemotherapy and a significant al., 2007) antitumor effect in mice. Thyme extract In vivo Human lung cancer cell line ↑anti-inflammatory properties by ↓the NF-κB (Oliviero et al., (H460) p65 and NF-κB p52 transcription factors 2016) protein levels followed by ↓pro-inflammatory cytokines (IL-1 beta and IL-8), and Muc5ac secretion in human normal bronchial and tracheal epithelial cells. T. thymol, T. linalool, and In vitro MCF-7 breast cancer cells- HeLa ↓HeLa cervical cancer and MCF-7 breast (Deering et al., T. thujanol. cervical cancer cancer cell viability by approximately 20% 2017) after 24 hours. Figure 5. The possible mechanisms of action of thyme, quince and indigo Efficacy of some plants and herbs in cancer therapy for humans and animals 333 Thyme (Thymus vulgaris) data a vailability statement Thyme (Thymus vulgaris L.) is a Mediterranean aro- No data are available. matic herb. T. vulgaris is the most common variety. 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Wang X., Bai H., Zhang X., Liu J., Cao P., Liao N., Zhang W., Wang Received: 3 X 2022 Z., Hai C. (2013). Inhibitory effect of oleanolic acid on hepato- Accepted: 21 X 2022 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Animal Science de Gruyter

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Abstract

Ann. Anim. Sci., Vol. 23, No. 2 (2023) 315–338 DOI: 10.2478/aoas-2022-0078 The efficacy of applying some planTs and herbs in cancer Therapy for humans and animals – a comprehensive review 1♦ 2 3 4 5 6 Mohamed E. Abd El-Hack , Manal A. Alfwuaires , Muthana M. Jghef , Asmaa F. Khafaga , Sameh A. Abdelnour , Mahmoud Abdel-Hamid , 1 2 7 8,9♦ 10 11 Mahmoud Alagawany , Abdulmohsen I. Algefare , Mashael M. Alnamshan , Mohamed S. Imam , Mohammed Gamal , Ahmad E. Elesawi , 12,13 Mohammad H. Abukhalil Poultry Department, Faculty of Agriculture, Zagazig University, Zagazig 44511, Egypt Department of Biological Sciences, Faculty of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia Department of Radiology, College of Medical Technology, Al-Kitab University, Kirkuk 36001, Iraq Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina 22758, Egypt Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig 44519, Egypt Dairy Science Department, Faculty of Agriculture, Cairo University, Giza, 12613, Egypt Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia Department of Pharmacy Practice, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia Department of Clinical Pharmacy, National Cancer Institute, Cairo University, Egypt Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Alshaheed Shehata Ahmad Hegazy St., 62514, Beni-Suef, Egypt Project Management and Sustainable Development Department, Arid Land Agriculture Research Institute, City of Scientific Research and Technological Applications, 21934, Alexandria, Egypt Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma’an 71111, Jordan Department of Biology, College of Science, Al-Hussein Bin Talal University, Ma’an 71111, Jordan Corresponding authors: Mohamed S. Imam: soliman@su.edu.sa, Mohamed E. Abd El-Hack: dr.mohamed.e.abdalhaq@gmail.com abstract cancer is a challenging ailment and represents the main reason for death worldwide for humans and animals. although great develop - ments have hindered cancer progression, several adverse effects are associated with modern chemotherapy. natural remedies, such as the usage of medicinal plant or their products in cancer treatment, may decrease prejudicial side properties. recently, the modern research scheme and innovative screening practices for herbs or plants have enabled phytochemical discovery for the prevention and treatment of cancer. This criticism highlights herbs such as acacia, basil, black seeds, cedar, castus, ficus, garlic, ginger, indigo, onion, pomegranate, quince, and thyme, promising anticancer effects. The present review also revealed the mode of action of each herb as anticancer effects at level in vitro and in vivo studies. The item also totalizes the vital mechanisms and signaling molecules involved in preventing cancer diseases. This will fill the investigation gap in the exploration of using natural molecules and encourage researchers in clinical trials of anticancer agents from herbs for humans and animals. Key words: herbs, plants, anticancer, tumor, therapy, natural remedies Most people (70–80%) in the developing world de- (WHO, 2019). Reports documented that the annual world pend on complementary or alternative medicine (World market of alternative herbal medications was valued at Health Organization, 2000). The World Health Organiza- $90 billion in 2015, while it was $200 000 and 1 300 000 tion (WHO) outlines alternative medicine as the entirety in 2007 and 2009, respectively (WHO, 2019). There are of the knowledge, practices and skills, according to the many traditional medicines used worldwide, from Islam- experiences, theories, and views indigenous to various ic medicine and Tibbs Nabawi or medicine of the Prophet cultures, whether justifiable or not, applied in the main - (AlRawi and Fetters, 2012), that include herbs and plants tenance of health as well as in the diagnosis, prevention, of various biological events that may be beneficial for enhancement or therapy of mental and physical diseases. human health. In the current review, we will discuss the Traditional or alternative medicine differs significantly anticancer activity of some herbs and plants declared in from culture to culture and region to region, as they are the holy Quran and prophetic Hadith. affected by many features including history, culture, per- Recently, several scientific interpretations mentioned sonal attitudes, and philosophy (WHO, 2000). Based on that herbal remedy is an important alternative tactic in the WHO reports, the market value of herbal medications the therapy of cancer (Dhanjal et al., 2021; Rana et al., has also augmented tremendously in the last few years 2021). These significant properties of some herbs in can- 316 M.E. Abd El-Hack et al. cer therapy might be associated with their anticancer a masking agent for bitter substances (Gebriel, 2011). As profits and other related pharmacological events, which reported by Roothaert and Franzel (2001), the usage of have established a prodigious deal of consideration for root decoction incorporated with leaves of Combretum their health usefulness (Roy et al., 2010; Khan et al., glutinosum and curdled milk presented strong diuresis. 2022). Moreover, herbal therapy preserves individuals’ As reported by various researchers, the anticancer activi- fertility and health, cures diseases, and even evades, ties of A. seyal are presented in Table 1. inhibits, or reduces cancer progress without bringing toxicity or side effects (Khan et al., 2022; Muhammad Table 1. The potentiality of anticancer activities of Acacia seyal et al., 2022). Studies indicated that more than 60% of based on the in vivo and in vitro studies cancer patients used herbs in their cancer therapy pro- Extract/active Study Cancer cell Mechanisms tocols (Khan et al., 2022; Muhammad et al., 2022; Tan References ingredient type type of action et al., 2022). So, the present review article hypothesizes Hydroethanolic In vitro MCF-7 cells- ↑Cytotoxicity (Zingue et that using certain plants, herbs or their derivatives has extract breast cancer al., 2018) a positive role in modern cancer therapy. In this criticism, cells we deliberate the uses of some herbs in the embattled Hydroethanolic In vivo 7,12-dimeth- ↓Tumor (Zingue et therapy of cancer disease in various kinds of tumor cells extract ylbenza-anthra- progression al., 2018) based on anti-apoptotic or antioxidant agents, as well as ceneDMBA- induced breast facts on their toxicity and safety. hyperplasia Lectin In vitro Hepatocellular ↓Bcl-2, ↑P53 (Patel et al., cancer cell apoptosis carcinoma 2014) Carcinogenesis is an imbalance between cell de- (HepG-2), velopment and cell death that accelerates cancer cell HCT-116 proliferation. Cancer can be observed as the result of (colorectal carcinoma) and a sequence of genetic fluctuations during which a nor - MCF-7 (breast mal cell is converted into a malignant one, while evasion cancer) of cell death is one of the indispensable fluctuations in Methanolic In vitro A549 (lung ↑Cytotoxicity (El-Hallouty a cell that causes this malignant transmutation (Hanahan extract of leaves carcinoma) et al., 2015) and Weinberg, 2000). Hence, inhibition of apoptosis or and branches and HepG-2 its resistance is vigorous in carcinogenesis progression. (hepatocellular carcinoma) Caspases are fundamental agents in the machinery of ap- optosis, as they are both the initiators and executioners. Specifically, caspase enzymes can be activated through three pathways. The two generally described initiation Zingue et al. (2018) evaluated the in vivo and in vitro tracks are irrelevant (or death receptor) and intrinsic (or anticancer properties of hydroethanolic extract of A. seyal mitochondrial) tracks of apoptosis. on breast cancer. The cytotoxicity action of A. seyal stem Consequently, both tracks ultimately lead to a com- bark extract was estimated via a resazurin reduction test munal track or the execution stage of the apoptosis pro- in different cell lines. The A. seyal extract meaningfully cess. The third track’s less well-recognized initiation is decreased tumor incidence in rats by 62.1% and 65.8% the intrinsic endoplasmic reticulum pathway (O’Brien for 150 mg and 300 mg/kg doses, respectively. They also and Kirby, 2008). Generally, the mechanisms by which reported that the A. seyal extract showed IC50 of 100 in cancer cells evade apoptosis may be regarded as the in- MCF-7 cells after 24 h. Moreover, A. seyal showed sub- terrupted equilibrium of pro-apoptotic and anti-apoptotic stantial protection against DMBA-brought breast hyper- mediators, reduced caspase function and weakened death plasia in rats, with an optimum result at 300 mg/kg level. receptor signaling. This imbalance between pro-apoptot- Likewise, the cytotoxicity of the recombinant lectin ic and anti-apoptotic elements promoted the survival and extracted from A. sayel was executed on MCF-7 (breast proliferation of cancer cells (Taylor et al., 2008). cancer), HepG-2 (hepatocellular carcinoma), HEP-2 (lar- ynx cancer) and HCT-116 (colon cancer) as reported by anticancer activities of some herbs and plants Patel et al. (2014). The purified lectin displayed a note- Acacia (Acacia seyal) worthy cytotoxic property on MCF-7 cells, with the IC In sub-Saharan Africa, the traditional system of medi- values for 100 µg/ml and 250 µg/ml for HepG-2 cells and cine Acacia seyal is used to treat several ailments such MCF-7, respectively. According to the previous work, the as dermatosis, infertility, and cancers. The stem is also lectin isolated form Acacia has beneficial anticancer prop- widely used to treat fungal infections, mainly genital erties, especially at a high dose of 100 µg/ml. Some of yeast infections and as chewing sticks with antimicrobial the mechanisms involved are suppression of the Bcl-2 and activity. A bark decoction is applied alongside leprosy and decreased expression of P53. Hence, A. sayel established dysentery diseases; as a stimulant and purgative agent; as possible cytotoxic events on the cancer cells HCT-116 an aphrodisiac with cytotoxic activity; as a pharmaceuti- (colorectal carcinoma), MCF-7 (breast adenocarcinoma), cal constituent in making emulsions and torches and as A549 (lung carcinoma) and HepG2 (hepatocellular carci- Efficacy of some plants and herbs in cancer therapy for humans and animals 317 noma). El-Hallouty et al. (2015) also confirmed the anti- ber of papillomas/mouse) and the deceased proportion of cancer activities of A. sayel at 1000 µg/ml against several tumor-bearing mice (Zeggwagh et al., 2007; Zarlaha et cancer cells, although the authors reported low activities al., 2014). that were less than 75% cytotoxicity. In an in vitro experiment, Karthikeyan et al. (1999) studied the anticancer activity of O. sanctum alongside Basil: sweet basil (Ocimum basilicum) and holy basil HFS cells (human fibrosarcoma cells). They found that (Ocimum sanctum) ethanolic extract of O. sanctum produced cytotoxic- Basil (family Lamiae) is a prevalent herb incorporat- ity impacts on HFS cells at 50 µg/ml levels. The cells ed with countless varieties of food preparations in Medi- exhibited shrunken cytoplasm, condensed nuclei, DNA terranean diets. For a long time, basil has been considered fragmentation, augmented lipid peroxidation levels, and one of the main essential oils-producing species connected depleted intracellular glutathione for the cytological at- to the genus Ocimum (Mohammadi et al., 2014). Moreo- tributes. Moreover, treating mice bearing solid sarcoma ver, studies have shown that basil and its extracts are also tumors with ethanolic and aqueous extracts of O. sanc- applied in the industrial trade, including pharmaceutical tum interceded a substantial decrease in tumor volume and cosmetic products (Grayer et al., 2002). Many studies and an augment in lifespan (Sridevi et al., 2016). Based have been published on the biological activities, including on the potential previous effects, it is clear that O. sanc- antibacterial, anti-inflammatory and antioxidant actions of tum extract has anticancer activity. basil essential oils and its components (Liu et al., 2012; Sridevi et al. (2016) studied the properties of alco- Mehana et al., 2020; Khafaga et al., 2019). Basil essential holic root extract of O. sanctum in NCI-H460 (human oils present several active components, such as eugenol, non-small cell lung carcinoma cell) by the generation geraniol, linalool, methyl chavicol and thymol, showing of ROS, cell viability assay, mitochondrial membrane several biological properties. Many investigated the anti- potential and apoptotic morphological changes. Admin- microbial action of eugenol with analgesic action for hu- istration of NCI-H460 cells with 150 μg/ml of O. sanc- mans (Koeduka et al., 2006) and the antioxidant action of tum extracts showed the lowest cell viability. Moreo- geraniol and linalool (Liu et al., 2012). ver, the O. sanctum extract (25–100μg/ml) presented a Others examined the usage of thymol, methyl chavi- substantial augment in ROS synthesis, inhibited cell col, and linalool for skin protection alongside all causes viability, increased apoptotic cell, loss of mitochon- of environmental skin aggressors and handling of dif- drial membrane potential, and colony-making abil- ferent dermatological syndromes (Huang et al., 2015). ity in NCI-H460 cells. It is interesting to note that O. Essential basil oils are also used in folklore medicine sanctum triggered loss of NCI-H460 cell, which is the to manage various human disorders such as cardiovas- potentiality of its anticancer activity. In another ex- cular and diabetes diseases (Zeggwagh et al., 2007). Ba- periment, Magesh et al. (2009) confirmed that O. sanc- sil has antioxidant, antimicrobial and antitumor ac- tum brings apoptosis in A549 cells via a mitochondrial tivities. Because basil is widespread worldwide, it is caspase-dependent way and hinders the in vivo (ani- easy to discover the potential activity of its essential mal model) development of Lewis lung carcinoma, oils. These biological properties of basil or its essential indicating that O. sanctum can be useful for treating oil might be attributed to its aromatic compounds and lung carcinoma as a chemo-preventive agent. Addi- phenolic acids (Zeggwagh et al., 2007; Zarlaha et al., tionally, the study implemented by Kwak et al. (2014) 2014). recommended that the anti-metastatic machinery of O. Taie and Radwan (2010) studied the upshot of the es- sanctum is interceded by repression of PI3K/Akt in sential oils of sweet basil obtained from Egypt, which osteopontin-treated lung cancer cells (NCI-H460). Ta- are extracted by hydro-distillation of the basil leaves. Re- ble 2 lists in vitro and in vivo studies that show basil’s sults showed the activity of the essential oils on a line of anticancer activities (O. basilicum). Ehrlich ascites carcinoma cells (EACC), where different Several scientific experiments indicated that O. ba- doses of the essential oils highly influenced the viability silicum extract or its essential oils showed cytotoxic- of these cancer cell lines by measuring the % of dead ity effects on MCF-7 or MDA-MB-231 via induction of cells. Mahmoud (2013) studied the anticancer activities apoptosis pathways, including caspase-3, bax, bcl-2, and of basil essential oils (in vitro and in vivo). The previ- p53 genes, as well as induced anaphase/telophase stag- ous study exhibited that incubating NB4 and HL-60 cells es along with F-actin aggregation (Arshad Qamar et with basil essential oils at levels of 25–200 μg/ml for 24 al., 2010; Behbahani, 2014; Mohammadi et al., 2014). h decreased these cells’ viability. It was indicated that the These consequences support the antiproliferative and basil essential oil (200 μg/ml) induced the highest HL-60 anticancer activities of O. basilicum extract against dead cell (82.33%), as mentioned by Mahmoud (2013). numerous types of cancer cell lines. Zarlaha et al. (2014) Moreover, administration of EACC with basil essential examined the antiproliferative action of ethanolic extract oils at levels of 25–200 μg/ml for 12 h decreased the vi- and the essential oil of O. basilicum alongside four vari- ability percentages of these cells. In vivo results showed ous cancer cell lines in humans: FemX cells (melanoma), that basil leaf extract chemo-preventive action was mani- HeLa cells (cervix adenocarcinoma), SKOV3 cells (hu- fest from the deceased tumor burden (the average num- man ovarian) and K562 cells (chronic myelogenous leu- 318 M.E. Abd El-Hack et al. kemia). The dominant elements of the extract are caffeic wide, such as southern Europe and the Middle Eastern and rosmarinic acids, while the most abundant elements Mediterranean (Khare, 2004). Seeds of N. sativa and in the essential oil are linalool, eugenol, and isoeugenol. their oil have been broadly applied for several culinary Those phytochemicals displayed noteworthy cytotoxic ac- or therapeutic applications. N. sativa has biological and tion alongside human ovarian cancer (SKOV3) cell lines. therapeutic activities as an antioxidant, antimicrobial, Curiously, caffeic acid was reported to be in the identical analgesic, anti-inflammatory, diuretic, renal protective, choice with cisplatin alongside the four cell lines displaying antihypertensive, antidiabetic, immunomodulatory, bron- substantial anticancer properties. At the same time, isoeuge- chodilating, gastroprotective, hepato-protective, and an- nol showed a higher cytotoxic effect than eugenol. Moreo- ticancer (El-Far, 2015; El-Far et al., 2017). Although they ver, depending on the in silico modeling experiments, the contain a complex mixture of several compounds, thy- isoeugenol molecule can efficiently constrain cyclooxyge- moquinone (TQ) is undoubtedly its major active ingredi- nase and lipoxygenase enzymatic action. Mechanisms of ent (Hajhashemi et al., 2004). TQ has been described to action of acacia and basil are illustrated in Figure 1. possess potent anti-inflammatory effects, such as in cases of encephalomyelitis, edema, colitis, and arthritis via the black seed (Nigella sativa) reduction of inflammatory prostaglandins and leukot - Nigella sativa seed (black cumin or black seed) is an rienes (Hajhashemi et al., 2004), and anti-tumoral activ- annual flowering herb found in many countries world- ity (El-Far, 2015) (Table 5). Table 2. The in vitro and in vivo studies showing the anticancer activities of basil (Ocimum basilicum) Extract/active Mechanisms Plant Study type Cancer cell type References ingredient of action Sweet Basil (Ocimum Essential oils (crude) In vitro A line Ehrlich ascites ↓Cell viability (Taie and Radwan, basilicum) carcinoma cells (EACC) 2010) Essential oils (crude) In vitro and in vivo Human promyelocytic In vitro: ↑cytotox- (Mahmoud, 2013) leukemia cell lines icity (HL-60 and NB4) and In vivo: Ehrlich ascites carcinoma ↓Tumor develop- cells, EACC (animal ment and tumor model cancer cells) volume of mice Methanolic extract In vitro Human breast cancer ↑Apoptosis (Arshad Qamar et al., and active compound cells (MCF-7 cell lines) 2010) (ursolic acid) Crude essential oils In vitro Human breast cancer ↑Apoptosis (Mohammadi et al., from leaves cells (MCF-7 cell lines) 2014) Crude essential oils In vitro MCF-7 and MDA- ↑Apoptosis (Behbahani, 2014) MB-231 (breast cancer cell lines) Ethanolic extract and In vitro HeLa cells (cervix ↑Cytotoxic (Zarlaha et al., 2014) the essential oil adenocarcinoma), FemX cells (melanoma), SKOV3 cells (human ovarian cancer) and K562 cells (chronic my- elogenous leukemia) Holy Basil Ethanolic and aqueous In vitro and in vivo HFS cells (human In vitro: (Karthikeyan et al., (O. sanctum) extract of the basil fibrosarcoma cells) Morphologically the 1999) leaves Sarcoma-180 cells showed con- densed nuclei and shrunken cytoplasm ↓intracellular GPx and increased ROS In vivo: ↓Tumor volume Ethanolic root extract In vitro NCI-H460 (non-small- ↓Cell viability (Sridevi et al., 2016) cell lung cancer cell ↓Colony forming lines) capacity Ethanolic root extract In vitro A549 cells (adenocarci- ↑Apoptosis (Magesh et al., 2009) nomas’ human alveolar basal epithelial cells) Ethanolic root extract In vitro NCI-H460 cell line ↓PI3K/Akt (Kwak et al., 2014) Efficacy of some plants and herbs in cancer therapy for humans and animals 319 Figure 1. Anti-cancer mechanisms of action of acacia and basil Table 5. Anticancer activities of C. speciosus Extract/active ingredient Study type Cancer cell type Mechanisms of action References Diosgenin In vitro HepG2, HL-60, Saos-2 Inhibition in the cell viability and (Selim and Al and MCF-7 induction of apoptosis Jaouni, 2016) Dioscin In vitro Hela Induction of apoptosis (Selim and Al Jaouni, 2016) Methanol and hexane extracts (leaves) In vitro HepG2, THP-1, and Inhibition of cell proliferation (Selim and Al WI-38 Jaouni, 2015) Costunolide In vitro and in silico MCF-7 and MDA- Induction of apoptosis and (Pitchai et al., MB-231 Inhibition in the cell viability 2014) (Roy and Manik- kam, 2015) Methanol extract (leaves) In vitro HepG2 Cell proliferation inhibition (Singh et al., using MTT 2016) In breast tissue, it has promoted apoptosis via acti- studies in xenograft mice model of HCT-116 colon can- vation of the p38 phosphorylation MDA-MB-231 xen- cer cells (Shoieb et al., 2003; Gali-Muhtasib et al., 2008). ograft mice (Woo et al., 2013). Also, other molecular in DLD-1 human colon cancer cells, TQ promoted the mechanisms, including the downregulation of Akt and reduction in the generation of ROS and phosphorylation XIAP that promoted the expression of caspase-3, Bax, of JNK and ERK and elevated activity of caspase-3 and apoptosis index factor (AIF), cytochrome c and p27 -7 (El-Najjar et al., 2010). Different animal models have genes in MCF-7 and breast cancer (MDA-MB-231) cells been used to investigate the molecular mechanisms and (Rajput et al., 2013). Furthermore, in vitro results showed potential therapeutic effects of TQ on hepatocellular an elevated expression of PPAR-γ activity and lower ex- carcinoma (HCC), such as rats, mice and rabbits (Nagi pression of some related apoptosis genes, including Bcl- and Almakki, 2009; Sayed-Ahmed et al., 2010; El- 2, Bcl-xL, and survival in breast cancer cells (Woo et al., Sayed, 2011; Elbarbry et al., 2012; Raghunandhakumar 2013). Other studies on lung cancer showed decreased et al., 2013; Ashour et al., 2014). In Sprague Dawley expression of LPS-induced NF-B expression (Jafri et al., rats, Al-Dalaen (2014), extensive studies have shown 2010). The bulk of scientific research on colon and colo- lowered activities of CYP1A1 and CYP2E1 in different rectal cancers in vivo and in vitro has been recently ad- tissues such as liver, lung and stomach tissues. Prostate dressed. In a study by Jrah-Harzallah et al. (2013) Wistar cancer in vitro data showed a reduction in androgen re- rats showed repressed DMH-induced oxidative stress and ceptors, E2F-1- and E2F-1-regulated proteins (Kaseb et colon tumorigenesis, confirming the results from other al., 2007). 320 M.E. Abd El-Hack et al. Hydroalcoholic extract, n-hexane, and ethyl acetate aqueous extract, were cytotoxic to MCF-7 cells at low fraction in vitro recent research showed a lowered viabil- concentrations and improved the antitumor property of ity of the ACHN cell in a dose- and time-dependent man- doxorubicin in breast cancer cells (MCF-7) (Mahmoud ner without considerable cytotoxicity in the slandered and Torchilin, 2013). Table 3 depicts different studies renal epithelial cell (Shahraki et al., 2015, 2016). Other that demonstrated the potential anticancer activities of black seed preparations, such as the lipid fraction and Nigella sativa. Table 3. Anticancer activities of Nigella sativa Extract/active ingredient Study type Cancer cell type Mechanisms of action References 1 2 3 4 5 TQ In vivo MDA-MB-231 xenograft mice ↑p38, ↑ROS (Woo et al., 2013) (breast cancer) In vivo MCF-7 and MDA-MB-231 ↓XIAP, ↓Akt , ↑p27, ↑caspase-3 ↑Bax, (Rajput et al., 2013) (xenograft breast cancer mice) ↑cytochrome c, ↑AIF, In vivo Lung cancer ↓LPS-induced NF- B expression (Jafri et al., 2010) In vivo Colon cancer ↓DMH-brought ROS and colon tumori- (Jrah-Harzallah, et al., genesis in Wistar rats 2013) In vivo Mice model of HCT-116 colon ↓growth of tumor cells (Gali-Muhtasib et al., cancer cells 2008) In vivo Colon cancer ↓DMH-induced colon cancer promotion (Jrah-Harzallah, et al., 2013) In vivo Colorectal cancer (HCT-116) cells ↑p21 expression (Shoieb et al., 2003) and osteosarcoma cells G1 phase cell cycle arrest In vivo Hepatocellular carcinoma ↑expression of p21 (Raghunandhakumar et ↓expression of cyclin D1, and E. al., 2013) ↓Cdk4, ↓Ki67, ↓PCNA in hepatic tissues of rat; ↓the cyclinD1, ↓cyclin E, ↓PCNA in NDEA-induced rats In vivo Male Wistar albino rats Restored DENA-induced depletion of (Sayed-Ahmed et al., glutathione, reduced hepatic enzyme 2010) activities including ↑CAT, ↑GPx, ↑GST, and down-regulation of some genes In vivo HepG2 cells G2/M phase cell cycle arrest (Ashour et al., 2014) ↓p50, ↓p65, ↓IL-8, ↓CXCR1, and ↓CXCR2, ↑caspase-9, ↑caspase-3, ↑PARP, ↑TRAIL, ↓NF-B, ↓Bcl-2 In vivo Sarcoma 80 xenograft mice Mixture with diosgenin ↓tumor mass (Das et al., 2012) ↓volume and ↑apoptosis In vitro MCF-7, MDA-MB-231 and ↑apoptosis (Woo et al., 2013) BT-474 (breast cancer cell lines) ↑caspases-8, ↑caspases-9, ↑caspases-7 ↑PPAR-γ, ↓Bcl-xL, ↓Bcl-2, and ↓survivin In vitro HTLV-I-negative T-cell Induced mitochondrial-mediated apopto- (Dergarabetian et al., lymphomas sis via generation of ↑ROS 2013) In vitro NCI-H460 and NCI-H146 cells Promoted apoptosis and suppressed the (Jafri et al., 2010) synthesis of ↓Gro-alpha and ↓ENA-78 In vitro Primary effusion lymphoma Induced mitochondrial-mediated apopto- (Hussain et al., 2011) sis and TRAIL via deactivation of↑ROS and ↓Akt In vitro Prostate cancer ↓the development of G1 to S phase LN- (Kaseb et al., 2007) CaP prostate cancer cells ↓androgen receptors, ↓E2F-1, ↓E2F- 1-regulated proteins such as cyclin A, Cdk-2, and Cdk-4 In vitro p53-null MG63 and p53-mutant ↑G2/M arrest (Roepke et al., 2007) MNNG/HOS (human osteosar- ↑p21WAF1 coma cells ) Efficacy of some plants and herbs in cancer therapy for humans and animals 321 Table 3 – contd. 1 2 3 4 5 In vitro p53-null myeloblastic leukemia ↑caspases-8,3,9, and ↑Bax/Bcl-2 ratio (El-Mahdy et al., 2005) HL-60 cells In vitro Human colorectal cancer cells G0/G1 arrest (Gali-Muhtasib et al., (HCT-116) ↑p53 2004) ↑Bax/Bcl-2 ratio In vitro Mouse papilloma carcinoma cells G0/G1 arrest, ↑p16, ↓cyclin D1 (Gali-Muhtasib et al., (SP-1) G2/M arrest, ↑p53, ↓cyclin B 2008) In vitro Colorectal cancer cells (p53-null ↑apoptosis (Gali-Muhtasib et al., HCT-116 cells) 2008) In vitro U266 multiple myeloma cells ↓STAT3 (Li et al., 2010) ↓cyclin D1, ↓Bcl-2, ↓Bcl-xl, and ↓sur- vivin ↓Src, ↓Akt and ↓Jak2 ↓VEGF In vitro FG/COLO357 (pancreatic cancer ↓migration of cancer cells (Torres et al., 2010) cells) ↓Mucin-4, and ↑JNK In vitro KBM-5 human myeloid cells ↓NF-kB-regulated gene products and (Sethi et al., 2008) ↓NF-kB activation, ↓TNFα-induced expression of ↓VEGF, ↓expression of MMP-9, ↓transcripts of XIAP, Bcl-xl, Bcl-2, IAP2, IAP1, and survivin In vitro M059J and M059K glioblastoma ↓telomerase and caused telomere attrition (Gurung et al., 2010) cells In vitro DLD-1 human colon cancer cells ↓phosphorylation of ERK and JNK (El-Najjar et al., 2010) ↑activation of caspase-3, and -7 and ↑generation of ROS In vitro SiHa human cervical squamous ↓expression of Bcl-2, ↑expression of p53; (Ng et al., 2011) carcinoma cells ↑Sub-G1 arrest In vitro MCF-7 cells ↓mRNA expression of CYP 1A1 and (Motaghed, et al., 2014) UGT1A8 (Kundu et al., 2014) (Rajput et al., 2013) In vitro HaCaT cells ↑Protein and mRNA expression of HO-1 (Kundu et al., 2014) In vitro Breast cancer cells (T47D and ↓expression of cyclin D1, E, Bcl-2 and (Rajput et al., 2013) MDA-MB-468) survivin ↑expression of p27; ↑Bax, ↑cytoplasmic cytochrome c; ↑caspase 3 Induced G1 phase cell cycle arrest ↓phosphorylation of GSK3, PTEN, Akt, and PDK1 In vitro PBD of Plk1; HeLa Induction of mitotic arrest, ↓Polo box (Reindl et al., 2008) domain function, Plk1 activity. meddling with Plk1 localization to centrosomes In vitro Multiple myeloma cells phosphorylation of STAT3, ↓expression (El-Far et al., 2016) of Bcl-2 and Bcl-xl. ↓F-actin polymerization In vitro HeLa cells ↓expression of NF-B. (Sakalar et al., 2013) ↑pro-apoptotic genes, CASP1, BIK, FASL In vitro A431 and Hep2 cells ↓phosphorylation of JNK and Akt (Das et al., 2012) ↑Sub-G1 arrest and TUNNEL positivity; ↑cytochrome c,↑Bax/Bcl-2 ratio, and activation of caspases In vitro Human neuroblastoma cells ↓XIAP and VEGF proteins, ↓expres- (Paramasivam et al., sion of XIAP ↓mitochondrial membrane 2012) potential. ↑Bax/Bcl-2 ratio; ↑activation of caspase-9 and -3. In vitro Glioblastoma cells ↓Secretion and activity of MMP-9 and -2, (Kolli-Bouhafs et al., ↓phosphorylation of ERK and↓FAK. 2012) 322 M.E. Abd El-Hack et al. Table 3 – contd. 1 2 3 4 5 In vitro Pancreatic ductal adenocarcinoma ↓histone deacetylase (HDAC) activity, (Chehl et al., 2009) (PDA) cells PDA, MCP-1, ↓Cox-2, ↓TNF-alpha, and ↓interleukin (IL)-1beta. ↑histone hyperacetylation, ↑p21 WAF1 expression. In vitro Human HL-60 leukemia, 518A2 ↑ROS and ↑apoptosis related to DNA (Effenberger et al., melanoma, multidrug-resistant tearing, ↓MMP and 2010) KB-V1/Vbl cervix, and MCF-7/ Topo breast carcinomas, non- malignant human foreskin fibroblasts In vitro and in Gastric cancer cells ↓Tumor growth in xenograft mice and (Lei et al., 2012) vivo ↑5-FU-induced apoptosis. In vitro and in SaOS-2 cells and mice ↓Expression of CD34, NF-B, and VEGF. (Peng et al., 2013) vivo Lipid fraction and aqueous In vitro Human MCF-7 breast cancer cells Cytotoxic to MCF-7 cells at low concen- Mahmoud and (Torchi- extract trations lin, 2012) ↑Antitumor activity of doxorubicin Hydroalcoholic extract of In vitro Human renal adenocarcinoma ↓Cell viability of ACHN. (Shahraki et al., 2015) N. sativa (ACHN) and normal renal epithe- Apoptotic effect of total extract in ACHN lial (GP-293 cell lines) cells compared with the GP-293 cells Hydroalcoholic extract In vitro ACHN cell (normal renal epithe- ↓ACHN cell viability and no cytotoxicity (Shahraki et al., 2016) (30% distilled water and lial). in GP-293 cells 70% alcohol) Seeds of N. sativa in In vitro Hepatocarcinogenesis ↓liver cancer in male Wistar rats (Iddamaldeniya et al., combination with Smilax ↓number of cells/cm2 of the positive foci 2003) glabra rhizome and ↓DEN-induced GST-P positive foci Hemidesmus indicus root N. sativa plant extract In vitro Human hepatoma HepG2 cells ↓DNA synthesis (Thabrew et al., 2005) induced cell apoptosis and/or necrosis N. sativa extracts In vitro Human breast cancer MDA- ↓the proliferation of human breast cancer (Dilshad et al., 2012) MB-231 cell cells through the induction of apoptosis Aqueous and alcohol In vitro MCF-7 breast cancer cells ↓the potency and survival (Farah and Begum, extracts 2003) A crude gum, a fixed oil In vitro MDR (human tumor cell lines) Cytotoxic effect through ↑cell accumula- (Worthen et al., 1998) and two purified compo - tion nents of N. sativa seed, TQ, and dithymoquinone N. sativa seed oil (NSO) In vivo Colon carcinogenesis in Fischer ↓cell proliferation in the colonic mucosa (Salim and Fukushima, 344 rats 2003) In vitro HEK293, MCF-7, A-549 and ↓percentage cell viability of MCF-7, (Al-Oqail et al., 2017) HepG2 cell lines A-549, and HepG2 cells, ↓GSH, ↓MMP, ↓bcl-2 ↑ROS, LPO , ↑p53, caspase-3, 9, and bax. In vitro Human fibro- ↓u-PA (urokinase-type plasminogen (Awad, 2005) sarcoma cell line, HT1080 activator) ↓PAI-1 (plasminogen activator inhibitor type 1) ↓t-PA (type plasminogen activator) In vitro Human monocyte and mac- ↓cell growth and differentiation in mono- (Mat et al., 2011) rophages cyte and monocyte-derived macrophage An experiment on male Wistar rats found that the dithymoquinone and TQ of N. sativa seed produced mixture containing seeds of Smilax glabra rhizome, N. a cytotoxic effect through increased cell accumulation sativa, and Hemidesmus indicus root has repressed hepa- in parental and multi-drug resistant (MDR) human tu- tocarcinogenesis (Iddamaldeniya et al., 2003). Another mor cell lines (Worthen et al., 1998). Finally, numerous mixture containing crude gum (as a fixed oil) and both in vivo and in vitro data promoted the high therapeutic Efficacy of some plants and herbs in cancer therapy for humans and animals 323 value of N. sativa seed oil in the induction of apoptosis and 13 ug/mL and IC50 values extending between 5 and repression of cell proliferation in the colonic mucosa and 7 ug/mL (Taleb et al., 2014). Furthermore, the es- (Salim and Fukushima, 2003), HEK293, A-549, HepG2, sential oil of C. libani was also cytotoxic alongside and MCF-7 cell lines (Al-Oqail et al., 2017), human drug-sensitive CCRF/CEM acute lymphoblastic leu- fibrosarcoma cell line, HT1080 (Awad, 2005), and hu- kemia cells and their multidrug-resistant P-glycopro- man monocyte and macrophages (Mat et al., 2011). tein-expressing subline, CEM/ADR5000 (Saab et al., 2012). cedar (Cedrus libani) Cedrus libani is one of the four Cedrus species costus ( Costus speciosus) (Pinaceae). C. libani and the other three naturally exist Costus speciosus (Family: Costaceae) is an impor- in the Mediterranean Sea area: C. libani in Turkey, Leb- tant medicinal plant known as spiral ginger. C. speciosus anon, and Syria, C. atlantica in Morocco and Algeria, is broadly applied as a folk medicine for treating various and C. deodara in the Himalaya Mountains, while C. complaints (Pawar and Pawar, 2014). It is widespread in brevifolia, on Cyprus Island (Abd El-Hack et al., 2016, tropical and subtropical regions of Africa, the Americas, 2018, 2020, 2021). It is a perpetual tree with a thick and Asia, particularly in India, Indonesia, Sri Lanka, and branch extended horizontally, a short and wide trunk, Malaysia (Specht and Stevenson, 2006; El-Far et al., and a broad corona with a pyramidal shape. The length 2016). of this plant reaches 20–40 m and up to 3 m in diameter, The rhizomes of the plant are characterized as bit- with glaucous blue-green leaves (8–25 mm), with a life ter and astringent. Pharmacological studies showed as long as 1500–2000 years (Kurt et al., 2008). C. libani that the rhizomes and root parts of C. speciosus pos- has been reported to have various biological activities; sess antioxidant, anti-stress, antibacterial, antifungal, tar is obtained from its steam wood and resinous root, and anti-inflammatory properties (Selim and Al Jaouni, and it generally possesses antibacterial and insecticidal 2015). Otherwise, the leaf extract of C. speciosus was activities (Saeed et al., 2017, 2018; Abdel-Moneim et shown to have probable in vitro anticancer action con- al., 2020; Reddy et al., 2016). Other studies revealed cerning hepatic cancer (El-Far et al., 2016). Addition- its antiulcerogenic properties (Yeşilada et al., 1999). ally, C. speciosus is a significant source of many mol- Anticancer activities of C. lebani are summarized in ecules possessing different pharmacological incomes, Table 4. such as saponins, B-sitosterol; diosgenin, dioscin, It was reported by Saab et al. (2011) that C. libani and prosapogenins A and B of dioscin, γ-tocopherol, ethanol and chloroform seed extract brought erythroid among others. Moreover, the major compound of differentiation and growth restraint in K562 cells (hu- C. speciosus oil was found to be costunolide (Selim man chronic myelogenous leukemia cells) with IC of and Al Jaouni, 2015). The therapeutic properties of C. 40.57 µg/mL and 69.20 µg/mL respectively. The speciosus extracts may be accredited by using vari- essential oil of C. libani also persuaded erythroid differ- ous ingredients such as flavonoids, alkaloids, sesquit- entiation and growth inhibition in K562 cells with IC of erpenes, and saponins. All conceivable up-regulation 23.38 µg/mL (Saab et al., 2012). of cellular apoptotic mediators as caspases, p21, p27, The 2-himchalene-7-ol (2HC7), a white crystal- p53, reactive oxygen species generation and others, line solid (125 mg, 0.3%), was isolated from the oil of characteristic of the anticancer properties of C. spe- C. libani by Taleb et al. (2014). The isolated 2HC was ciosus toward the down-expression of the anti-apop- then confirmed alongside colon (Caco-2) or brain (SF) totic mediators (El-Far et al., 2016). As seen in Ta- cancer cells at different levels extending between 1 and ble 5, we summarized the potential anticancer activities of 25 ug/mL. Results showed a noteworthy anti-prolif- C. speciosus according to the in vivo and in vitro ex- erative property with IC99 values ranging between 11 periments. Table 4. Anticancer activities of C. lebani Mechanisms Extract/active ingredient Study type Cancer cell type References of action Ethanol and chloroform seed extract In vitro in K562 cells (human chronic myelogenous leukemia ↓Cell growth (Saab et al., 2011) cells) Essential oil In vitro in K562 cells (human chronic myelogenous leukemia ↓Cell growth (Saab et al., 2012) cells) Essential oil In vitro CCRF/CEM acute lymphoblastic leukemia cells and ↓Cytotoxicity (Saab et al., 2012) CEM/ADR5000 (multidrug-resistant P-glycoprotein- effect expressing subline) 2-himachalene-7-ol In vitro SF (brain cancer cells) and Caco-2 (colon cancer cells) ↓Proliferation (Taleb et al., 2014) 324 M.E. Abd El-Hack et al. Diosgenin and dioscin have been reported to have 15–20 ft with several spreading branches and a trunk more anticancer activity and are considered of great inter- than 7 ft in diameter (Chawla et al., 2012). The utmost est to the pharmaceutical industry (Selim and Al Jaouni, imperative species of Ficus are F. racemose, F. elastica, 2016). Indeed, diosgenin induces apoptosis and inhibits F. bengalensis, and F. carica. Almost all plant portions, such cell viability in different cancerous cells (HepG2, HL-60, as leaves, fruits, bark, shoots, latex and seeds, are medici- and MCF-7 and Saos-2) (Selim and Al Jaouni, 2015). Si nal. The Ficus is a beneficial health plant applied widely in milarly, the anticancer activity via apoptosis induc- different industrial and pharmaceutical uses. This feature is tion and cell viability inhibition was described for Cos- due to its richness in vitamins, micro and macro minerals, tunolide in MDA-MB-231 and MCF-7 cells, shown water, fats and various phytochemicals such as flavonoids, in in vivo and in silico assays (Pitchai et al., 2014; Roy phenol, terpenoids, and other sources of calcium and fiber and Manikkam, 2015). On the other hand, dioscin – a (Caliskan, 2015). Hence, the hepatoprotective, antioxidant, derivative from diosgenin – was described to induce antidiabetic, anticancer, antiplatelet, anthelmintic, diuretic, apoptosis in HeLa cells through cyclooxygenase activ- hypolipidemia, and immunity activities of Ficus have been ity in osteosarcoma cells (Selim and Al Jaouni, 2016). studied by various investigators (Singh et al., 2016). Methanol and hexane extracts of C. speciosus leaves Several studies have reported the anticancer activi- were reported to have in vitro anti-proliferative effects on ties of ficus (Table 6). The constituents of ficus comprise a HepG2, WI-38, and THP-1 cells by inhibiting cell pro- combination of 6-O-acyl-beta-D-glucosyl-beta-sitosterols, liferation (Selim and Al Jaouni, 2015; Singh et al., 2016). the acyl moiety being mainly linoleyl and palmitoyl with The possible mechanisms of action of the black seed, Ce- minor amounts of oleyl and stearyl, displayed powerful drus libani, and Costus speciosus are illustrated in Figure 2. cytotoxicity properties on various cell line cancer cells (Rubnov et al., 2001). The F. carica fruits and leaves la- ficus (Ficus carica) tex also showed antiradical activity and antiproliferative Ficus (Ficus carica) is one of the copious kinds of me- activity against A375 (human melanoma cell line) after ex- dicinal plants comprised of about 800 species of shrubs, posing to irradiation at a specific UVA at minimum IC50 woody plants and trees mostly found in tropical and sub- values (Menichini et al., 2012). The anti-proliferative ac- tropical regions worldwide (Herre et al., 2008). Ficus rep- tion of F. carica latex and F. carica latex-temozolomide resents one of the most common traditional Mediterranean mixture was examined in several cell lines, such as U-87 plants in the Moraceae family. F. carica tree normally has MG, T98G, and U-138 MG glioblastoma. Figure 2. The possible mechanisms of action of black seed, Cedrus libani and Costus speciosus Table 6. Anticancer activities of Ficus Study Mechanisms Extract/active ingredient Cancer cell type References type of action 6-O-acyl-beta-D-glucosyl-beta-Sitosterols In vitro Lymphoma cell (Raji Burkitt B), DU-145 prostate Not reported (Rubnov et al., 2001) cancer and MCF-7 cells, Burkitt B cell lymphoma (DG-75), Jurkat T-cell leukemia Latex-temozolomide mixture In vitro U-138 MG, T98G, and U-87 MG glioblastoma Cell death (Tezcan et al., 2015) Leaves, bark and wood extracts In vitro Human melanoma ↓proliferation (Conforti et al., 2012) Bergapten and psoralen from F. carica leaves In vitro Triple-negative breast cancer (MDA-MB-231 cells) Not reported (Zhang et al., 2018) Ficutirucins A-I but ficutirucins A, B, C, F, G In vitro MCF-7, HepG-2, and U2OS ↓Cytotoxicity (Jing et al., 2015) and I possessed anticancer effects effect Efficacy of some plants and herbs in cancer therapy for humans and animals 325 F. carica latex administration produced substantial 2013). Both rodent and human studies have reported that cell death in glioblastoma multiforme cells with various garlic or its preparations can suppress the development of responses to F. carica latex-temozolomide mixture (Tez- chemically encouraged tumors in hepatic tissues (Kweon can et al., 2015). Khodarahmi et al. (2011) also affirmed et al., 2003), esophagus (Chen et al., 2009), stomach (Tu- the anticancer properties of F. carica latex on human rati et al., 2015), colorectum (Galeone et al., 2006), blad- cancer cells using HeLa cell line in vitro using the MTT der (Turati et al., 2015), and prostate (Hsing et al., 2002). assay. Leaves were revealed to have repression of peroxi- The possible mechanisms of action of fig and garlic are dation and the highest anti-radical action with IC values illustrated in Figure 3. of 1.48 and 64 μg/ml, respectively. Conforti et al. (2012) found that the leaves had the maximum anti-proliferative ginger (Zingiber officinale ) action with an IC value of 3.92 μg/mL. Psoralen and Ginger (Zingiber officinale ) is also a very prevalent bergapten are the dominant active molecules in F. carica plant that belongs to the family Zingiberaceae. It origi- leaves with general anticancer action on MDA-MB-231 nated in South-East Asia and its rhizome is applied in (triple-negative breast cancer cells), representing that numerous countries as a spice and food flavor (Park and these two components might show imperative function Pezzuto, 2002). Several health-promoting perspectives in anticancer activities of F. carica leaves (Zhang et al., of ginger are accredited to its rich polyphenols, such as 2018). Likewise, the anticancer efficiency of ethanolic gingerols (mainly in the fresh rhizome) and shogaols (de- extract of pulverized fruit of F. carica was examined on hydrated gingerol derivatives in dried rhizome) (Jolad et breast cancer cell lines MCF-7. The extract presented al., 2004; Jiang et al., 2006). robust anti-tumor actions at 85.5 and 89% suppression Using ginger can be considered safe, although fur- after 24 and 48 hours, respectively, at levels of 1000 μg/ ther understanding of its mechanisms of action is needed. mL, while the low level showed the proportion inhibition Ginger has several therapeutic uses, including degenera- was 76, 80.5 and 82.5% at 24, 48, and 72 hours, respec- tive and cardiovascular syndromes, vomiting, digestive tively (Jasmine et al., 2015). Jing et al. (2015) examined health, diabetes mellitus, and even cancerogenic (Jiang et the cytotoxic activities of many molecules isolated from al., 2006; Patel et al., 2007). It also possesses anti-inflam - F. carica fruits, ficutirucins A-I, and these molecules ex- matory, anti-oxidative properties and antimicrobial po- hibited moderate cytotoxic actions with IC values of tential against gram-positive and gram-negative bacteria 11.67–45.61 μM alongside many cancer cell lines in hu- (Jiang et al., 2006; Patel et al., 2007; Singh et al., 2008). man such as U2OS, MCF-7, and HepG-2. Evidence from both in vivo and in vitro studies (Table 8) recommends that ginger and its active components con- garlic ( Allium sativum) strain the development of several cancer types, includ- Garlic (Allium sativum L.), originally from Asia, is ing breast, renal, cervical, colon, gastric, oral, pancreatic, a bulbous plant that can easily grow in mild climates. prostate, hepatic, and brain cancer (Tuntiwechapikul et Garlic has played an important dietary role as a spice al., 2010; Kim et al., 2014; Wu et al., 2015). Shogaol sup- and food additive (Eja et al., 2007). Garlic can be con- presses the growth and brings apoptosis of non-small cell sumed in the form of raw garlic, raw garlic homogen- lung cancer cells (Kim et al., 2014; Wu et al., 2015) and ate, an aqueous extract of garlic, garlic oil, crushed or enhances gemcitabine properties in human pancreatic chopped garlic and aged garlic extract. The main com- cancer, such as BxPC-3 and PANC-1 (Gan et al., 2011). pound present in intact garlic is alliin. Alliinase enzyme produces allicin from alliin when garlic is chopped or indigo (Indigofera tinctoria) crushed. Also, other sulfur compounds such as diallyl Indigofera tinctoria belongs to the family Fabaceae disulphide, S-allylcysteine, and diallyl trisulfide contrib- and is a widely distributed one- to two-meter height ute to some of the garlic effects (Lanzotti et al., 2012). shrub found in several regions, Southeast Asia and the Several medicinal and therapeutic effects of garlic or gar- Indian subcontinent, Africa, and America (especially in lic preparations have been reported. These effects range tropical areas). The alcoholic extract of the leaves has from improving detoxification of foreign compounds and an antihepatotoxic influence on carbon-tetrachloride and hepatoprotection or cardiovascular protection to anti- D-galactosamine-triggered hepatic damage (Sreepriya oxidant effect, antimicrobial effect, or even suppressing et al., 2001). Indigtone, an active constituent located in the risks of cancer (Colín-González et al., 2012). leaves has hepatoprotective activity (Singh et al., 2001). Table 7 summarizes studies of the anticancer activities Moreover, I. tinctoria influences chronic myelogenous of garlic. leukemia (Steriti, 2002). Indirubin showed noticeable re- The cancer-preventive effects of garlic or its prepa- pression of Walker carcinoma and Lewis lung carcinoma, rations that contain allylsulfide derivatives have been signifying that I. tinctoria has considerable antineoplas- extensively reported. Some studies on garlic anticancer tic activity (Han, 1994). Another type of indigo called action have shown that it can be established via the mod- Polygonum tinctorium belongs to the family Polygonace- ulation of several molecular mechanisms responsible for ae. In its leaves, P. tinctorium stores large quantities of carcinogenesis, including DNA adduct formation, mu- a colorless glycoside, indican (indoxyl beta-D-glucoside) tagenesis, cell proliferation and angiogenesis (Capasso, (Selvius et al., 2011). 326 M.E. Abd El-Hack et al. Table 7. Anticancer activities of garlic Extract/active ingredient Study type Cancer cell type Mechanisms of action References Garlic products In vivo Prostate cancer ↓prostate cancer risk. (Hsing et al., 2002) In vitro Fresh garlic In vivo Prostate cancer ↓ratio of prostate cancer by 30-50%. (Hsing et al., 2002) Garlic products Stomach cancer ↓Death ratio by 10-folds (Setiawan et al., 2005) In vivo ↓risk of stomach cancer. Fresh garlic In vivo Gastric cancer ↓nitrate-reducing bacteria and ↓nitrite formation. (Turati et al., 2015) Raw garlic Esophageal cancer ↓the risks of esophageal cancer. (Galeone et al., 2006; In vitro Chen et al., 2009) Garlic products In vitro Pancreatic cancer ↓risk of pancreatic cancer due to garlic use. (Chan, 2005) Garlic products In vitro Colorectal cancer ↓risk of colorectal cancer (Galeone et al., 2006) Figure 3. The possible mechanisms of action of fig and garlic Table 8. Anticancer activities of ginger Extract/active ingredient Study type Cancer cell type Mechanisms of action References Shogaols In vivo Lung cancer ↓tumorigenesis, ↓NF-B activation, ↓COX-2, and ↓iNOS, (Kim et al., 2014) ↓development and apoptosis biomarkers of cancer cells via Akt1/2 pathway Shogaols In vitro Pancreatic cancer ↓Bcl-2, MMP-9, cIAP-1, cyclinD1, surviving, XIAP, and (Gan et al., 2011) Bcl-2. ↓Antitumor activity, ↓TLR4/NF- B signaling ↑PANC-1 and BxPC-3 ↓TLR4/NF- B, ↓formation of cancer cell colony. Ethyl acetate In vitro Lung cancer ↑cell death, ↓hTERT (human telomerase reverse tran- (Tuntiwechapikul (A549) scriptase) and c-Myc. et al., 2010) Young Zingiber officinale and In vitro MCF-7, and PC- ↑cytotoxic effect against MCF-7, PC-3, and A-549 cancer (Zu et al., 2010) its essential oil 3, A-549 cells; ↓risk of hepatic cancers Ethanol extract In vitro Colon cancer ↓mTOR and Wnt/ catenin signaling pathways, ↑apoptosis in (Abdullah et al., HT29 cells. 2010) ↓S-phase population in HT29 and HCT-116 cells. Efficacy of some plants and herbs in cancer therapy for humans and animals 327 The indigo plant has been used in medicine in Japan, ence of leaf extract on NCI-H69 (lung cancer cell line) China, and Korea for over a thousand years (Cooksey, was found to be eminent by augmenting the level of 2012; Heo et al., 2012). The main bioactive substances leaf extract. in the indigo plant are mostly flavonoids, polyphenols, Heo et al. (2014) investigated the cytotoxic influ- tannins, and flavonols (Heo et al., 2013). In addition, this ences of the ethanol, water, and methanol extracts of plant’s most beneficial active principles are indirubin, in- leaves, flowers, seeds, and stems of indigo on HEK 293 digo, kaempferol, and tryptanthrin (Cooksey, 2012). (human renal cell line) and suppressor influences on the Kameswaran and Ramanibai (2008) explored indigo proliferation of MCF-7 (breast carcinoma cells), HeLa aerial parts’ potential anticancer activity (against human (cervical carcinoma cells), HCT-116 (colon cancer cell), non-small cell lung cancer cells A-549). Interestingly, fla- Hep3B (liver carcinoma cells), SNU-1066 (laryngeal vonoid molecules isolated from the ethanolic extract of cancer cell) and SNU-601 (gastric cancer cell). The high- indigo considerably repressed the proliferation of A-549 est concentration of total polyphenols was detected in cells. Flow cytometric analysis revealed that methanolic methanol extracts of flowers and leaves. However, the extract of I. tinctoria stopped cell cycle development in methanol extract of seeds, flowers and leaves has the G0/G1 stage and boosted A-549 cell apoptosis. The au- highest proportion of flavonoids. The maximum antioxi - thors suggested that flavonoid screening of methanolic dant capacities were also detected in methanolic extracts extract of I. tinctoria action might contribute to its overall of leaves and flowers. The highest relation between the chemo-preventive impacts alongside lung cancer. They survival rates and the antioxidant abilities was in metha- might probably be measured for upcoming therapeutic nol extracts of leaves on HeLa cells (Heo et al., 2014). uses. So, in vitro studies showed that the indigo extracts were Oral administration of methanolic fraction of detected to be efficient in constraining the development I. tinctoria at levels 100 and 200 mg/kg markedly low- of cancer cells (Table 9). ered the increased level of uronic acid and hexosamine The use of naturally accessible fuels for nanoparti- content compared to vehicle-treated control one. The in cle solution combustion synthesis (SCS) has increased. vitro cytotoxic action of methanolic extraction of I. tinc- Many studies reported that biofuels have harmless en- toria on melanoma cells (B16F10) was recorded at 24.8 vironmental effects, but their tactical recompenses for µg/ml at IC50. Renukadevi and Sultana (2011) studied the synthesis of NPs have not been fully investigated. the cytotoxic, antioxidant and antibacterial activity of Prashanth et al. (2018) studied the usage of plant ex- the leaf extract of I. tinctoria. The cytotoxic activity of tracts as biofuels for the SCS of zinc oxide nanoparti- leaf extract was determined on a lung cancer cell line. cles (ZnNPs). The authors carried out the combustion The phytochemical examination found several active synthesis of ZnNPs by using aqueous and lactose leaf molecules like saponins, flavonoids, steroidal terpenes, extracts of Indigofera tinctoria, Melia azedarach, Abu- tannins, anthraquinone and phenols. The robust anti- tilon indicum as biofuels. A comparative analysis has oxidant activity of the indigo extract was detected at been conducted to comprehend the benefits of using –l 250 µg mL with an IC value of 51.66, which is more plant extracts over a biochemical as a combustion fuel than that of standard ascorbic acid. The cytotoxic influ- for synthesizing ZnNPs. Table 9. Anticancer activities of indigo Extract/active ingredient Study type Cancer cell type Mechanisms of action References The methanolic extract of aerial In vitro Human non-small cell Flavonoid fraction of methanolic extract (Kameswaran and Ra- parts of the plant Lung cancer cells a-549. of I. tinctoria prohibited cell cycle de- manibai, 2008) velopment in GO/G 1 Phase and induced a-549 cell apoptosis. ZnNPs synthesized using lactose In vitro DU-145 and Calu-6 cancer The machinery of apoptosis (Prashanth et al., 2018) and aqueous leaf extracts cells in cancer cells due to ZnNPs still not be- ing explored. I. tinctoria leaf extract and the In vitro Lung cancer cell line A549 Induce reactive oxygen species (Vijayan et al., 2018) nanoparticles of gold and silver by nanoparticles. It reasons reparations to the cellular con- stituent and leads to the cell death Water, methanol and ethanol In vitro Hek 293, HEP3b, MCF-7 Flavonoids and polyphenols in extracts of (Heo et al., 2014) extracts of flowers, leaves, stems, HCT-116, Hela, snu-1066, various parts of indigo. and seeds from indigo and snu-601. (P. tinctorium) Methanol and ethyl acetate from In vitro Calu-6 (human cancer cell Tryptanthrin and indirubin, both com- (Jang et al., 2012) the indigo powder, seeds, or the lines) and SNU-601 (human pounds originating from indican in the prolipid. gastric carcinoma) leaves of P. tinctorium are responsible for many of the biological activities of this Plant. 328 M.E. Abd El-Hack et al. pomegranate (Punica granatum) Moreover, the authors conducted antiproliferative eval- Pomegranate is a long-lived and drought-tolerant uation against Calu-6 and DU-145 cancer cells and detected small tree. It is mainly found throughout the Mediter- the higher anticancer action of ZnNPs ready utilization ranean, Iran, India, China, and the USA (Ercisli et al., biofuels. The biocompatibility of ZnNPs at lower concen- 2011). The pomegranate consists of different compart- trations was detected by blood hemolysis. Further studies ments: seed, juice, peel, and leaf. The chemical composi- would be needed to validate the potential benefits of natural- tion of the fruits depends on several factors, including ly offered fuel usage in SCS. Vijayan et al. (2018) reported the growing region, climate, cultivation practice, and the innovation of novel metal nanoparticles, explicitly gold storage conditions (Fadavi et al., 2005). The peel con- (AgNPs) and silver (AuNPs), from their salt by using leaf tains important bioactive constituents like flavonoids, extract of I. tinctoria. This leaf extract acts as a stabilizing phenolics, proanthocyanidins, ellagitannins, and other and reducing mediator for the creation of nanoparticles. The significant minerals. The edible part of the pomegran - antiproliferative influence of I. tinctoria leaf extract and the ate fruit is rich in several bioactive molecules such as nanoparticles were investigated in A549 (lung cancer cell). flavonoids and phenolics, mainly anthocyanins (Viuda- It was detected that the elevating concentration reduces cell Martos et al., 2010) that prevent lipid peroxidation of viability, and the pure leaf extract has a less toxic influence cells. Pomegranate seeds contain estrogenic compounds on cancer cells than nanoparticles. Studies have shown that like estrone and estradiol (Kim and Choi, 2009). The the IC value of AgNPs, and AuNPs (biogenic synthesis) by seed cover of the fruit contains delphinidin-3,5-diglu- I. tinctoria leaf extract are 56.62±0.86l g/ml, 59.33±0.57l g/ coside, the primary anthocyanin in pomegranate juice ml and 71.92±0.76l g/ml, respectively. Moreover, the syn- (Elfalleh et al., 2012). Pomegranate juice, pomegranate thesized metal nanoparticles showed high antimicrobial ac- extracts, and seed oil have interesting pharmacological tions. activities. Extracts of all parts of the pomegranate fruit have numerous biomedical applications and therapeutic onion (Allium cepa ) properties ranging from being utilized as a medication Onion, a biennial plant, generally adapts to temperate for dysentery, diarrhea, hemorrhage, acidosis, helminth environments with low water supplies. It is thought to infection, microbial infections, and respiratory patholo- have originated in central Asia (Zeng et al., 2015). On- gies (Kim and Choi, 2009) or even targeting a variety ion can be used in fresh, raw and processed forms. Be- of ailments including cardiovascular syndromes, Alz- sides its culinary uses, it is considered a good medicinal heimer’s disease, male infertility, aging, diabetes, and and therapeutic compound for many diseases (Nuutila AIDS or even cancer (Lansky and Newman, 2007; Ju- et al., 2003; Vidyavati et al., 2010). Onions are rich in renka, 2008). two bioactive ingredients, including flavonoids, such as Recently, pomegranates have been reported for their anthocyanins and flavanols, such as quercetin, and the wide range of anti-cancer properties, especially in breast sulfur-containing compounds (alk(en)yl cysteine sulph- and prostate cancers. Fermented pomegranate juice has oxides (ACSOs)) (Alagawany et al., 2014, 2016; Dosoky doubled the pomegranate extracts’ effect in constraining et al., 2021). The numerous reported health properties of the development of MCF-7 (breast cancer cells) via stim- onions in vitro and in vivo are due to their antioxidant, ulation of apoptosis (Mehta and Lansky, 2004; Jeune et hypocholesterolemic, hypoglycemic, and thrombolytic al., 2005; Bassiri-Jahromi, 2018). Pomegranate fruit has or even anticarcinogenic effects (Vidyavati et al., 2010). been reported to inhibit cell growth, induce apoptosis of Onions may have anticarcinogenic properties, as re- human prostate cancer, and prevent hepatocellular carci- ported in both animal and human trials against a wide noma in humans (Kaplan et al., 2001). Pomegranate ex- range of cancer types, such as esophageal, gastric, colo- tract has antiproliferative activity in non-small cell lung rectal, hepatic, renal, lung, bladder, breast, ovarian, and carcinoma cell lines both in a time- and dose-dependent brain cancer (Fukushima et al., 1997; Hsing et al., 2002; manner (Khan et al., 2008; Husari et al., 2017; Sharma Galeone et al., 2006; Millen et al., 2007). Table 10 shows et al., 2017). the anticancer activities of onion. In breast cancer, the Pomegranate fruit extract can be used in human lung tetrasulfide compound naturally occurring in onion can cancer therapy by inhibiting several signaling pathways inhibit the proliferation of both sensitive and resistant such as mitogen-activated protein kinases (MAPK), human breast carcinoma cells by targeting the enzymes PI3K/Akt, and NFκB (Khan et al., 2007). Pomegranate involved in the cell cycle (Galeone et al., 2006; Millen oil treatments have reduced tumor incidence and numbers et al., 2007). Several reports have concluded that onion in mice (Viuda-Martos et al., 2010; Elfalleh et al., 2012). or onion products can repress the growth of several hu- The bulk of investigations showed that the pomegranate man cancer cell lines, including stomach and colon cells pulp extract exerts anti-skin tumor-encouraging action in (Setiawan et al., 2005; Turati et al., 2015). Also, onion CD-1 mice (Pacheco-Palencia et al., 2008). Additionally, intake has been consistently associated with decreas- pomegranate seed oil supplementation improved the ex- ing the risk of colorectal cancer (Millen et al., 2007). pression of PPARα in the non-tumor mucosa and mean- A study by Hu et al. (1999) has described that dietary ingfully reduced the occurrence of colonic adenocarci- supplementation with onion products is associated with nomas (Kohno et al., 2004). The anticancer activities decreased brain cancer risk. Efficacy of some plants and herbs in cancer therapy for humans and animals 329 of pomegranate were detected by several authors granate can constrain the development of cancer cells (Table 11). In vitro experiments have revealed that pome- such as lymphoid cell line (K562- 4), EJ cell – UBUC granate juice possesses anti-inflammatory effects on the T24, glioma cells (U87MG), and J82 cell (Joseph et al., signaling proteins found in human colon cancer (HT-29 2012; Dahlawi et al., 2013). The possible mechanisms cell line) (Seeram et al., 2005). Several in vitro stud- of action of pomegranate and onion are illustrated in ies have reported potential machinery via which pome- Figure 4. Table 10. Anticancer activities of onion Cancer Extract/active ingredient Study type Mechanisms of action References cell type Onion products - organo- sulphur In vitro Breast ↓risk of breast cancer (Viry et al., 2011) compounds such as tetrasulfides In vivo cancer ↓the proliferation of sensitive and resistant human breast carcinoma cells by targeting the cell division cycle 25 phosphatases, crucial enzymes of the cell cycle Fresh onion In vivo Gastric ↓of nitrate-reducing bacteria and ↓nitrite formation. (Turati et al., 2015) cancer Fresh onion In vivo Prostate ↓risk of prostate cancer (Hsing et al., 2002) cancer Onion products and derivatives In vivo Colorectal ↓risk of colorectal cancer. (Millen et al., 2007) cancer Onion products – quercetin and In vivo Lung ↑anticancer properties as demonstrated in lung cancer (Vijayababu et al., 2006) derivatives cancer Onion – quercetin and luteolin In vivo Skin ↑anticancer properties as demonstrated in skin cancer. (Vijayababu et al., 2006) cancer ↓UVB-induced skin tumorigenesis in SKH-1 hairless mice via ↓PKCε and c-Src kinase activity. Onion products – onion peel – total In vitro Stomach ↓growth of several human cancer cell lines, including (Setiawan et al., 2005; phenolics and flavonoids cancer cells of the stomach and colon Turati et al., 2015) Onion – quercetin and derivatives In vitro Liver ↑anticancer properties as demonstrated in liver cancer (Fukushima et al., 1997) cancer Table 11. Anticancer activities of pomegranate Extract/active ingredient Study type Cancer cell type Mechanisms of action References 1 2 3 4 5 Juice, seed oil, In vitro Breast (MCF-7- MCF- ↓Growth of MCF-7 through ↑apoptosis. (Jeune et al., , 2005; fermented juice In vivo 7aro) ↓Expansion of new blood vessels. Bassiri-Jahromi, 2018) polyphenols, extract Seed oil, fermented juice In vitro Prostate (DU-145, PC-3) Patients with prostate cancer, pomegranate (Seeram et al., 2005) polyphenols, extract, juice has revealed substantial prolongation juice repetition time of prostate precise antigen. Fruit extract In vivo A549 lung carcinoma ↓H1299 cell survival by arresting cell (Khan et al., 2007; In vitro cells cycle progression in G2/M phase. Khan, et al., 2008; ↓HIF-1α and PHH3 expression. Husari et al., 2017; ↓cell proliferation, ↓pro survival path- Sharma et al., 2017) ways, ↓tumor growth in the nude mice, ↓formation of lung nodules. Seed oil, fruit extract, pulp extract In vivo Skin ↑interleukin 1 (IL-1) and IL-1 beta from the(Hora et al., 2003; cells in the mice and human’s macrophag- Afaq et al., 2005; In vitro es. ↑macrophages. Pomegranate pulp Pacheco-Palencia et extract contains anti-skin tumor promoting al., 2008) activity in CD-1 mouse by ↓biomarkers of tetra decanoyl phorbol 13-acetate (TPA)- induced tumor promotion. Seed-oil, juice In vivo Colon ↑PPARγ (Kohno et al., 2004; In vitro Pomegranate seed oil can↓azoxymethane- Adams et al., 2006) induced colon carcinogenesis. Pomegranate juice, total pomegran- In vitro Colorectal ↓NF-kB response element, and PJ also (Seeram et al., 2005; ate ellagitannins; punicalagin, ellagic Cancer (HT-29, HCT- ↓AKT stimulated by TNF-α. Adams et al., 2006) acid, pomegranate tannin extract 116, Punicalagin, EA, TPT and PJ SW620-HT-29) ↑apoptosis, PJ, TPT and punicalagin ↓NF- α mediated COX-2 protein expression 330 M.E. Abd El-Hack et al. Table 11 – cont. 1 2 3 4 5 P. granatum peels extract- In vitro Leukemia (K562- 4 ↓development of K562 cell line through (Joseph et al., 2012; pomegranate juice, polyphenols lymphoid cell line) cell cycle arrest at G2/M phase, Dahlawi et al., 2013) ↑apoptosis. ↓cellular proliferation Pomegranate extract, Pomegran- In vitro Hepatocellular carci- ↓Lipid and protein oxidation in hepatic (Kaplan et al., 2001) ate juice, bioactive components, noma tissues. resveratrol Prevention of hepatocellular ↓cell proliferation, control cell cycle development, and ↑apoptosis in rats. Punicalagin as a polyphenol isolated In vitro Glioblastoma (U87MG ↓U87MG cell viability (Wang et al., 2013) from P. granatum glioma cells) ↑Apoptosis, ↑AMPK/p27, ↑caspase-3 and 9, ADP-ribose ↑autophagy cell death via microtubule- associated protein light chain 3 II, LC3-II breakage. Pomegranate extract, pomegranate In vitro Bladder cancer (EJ cell – ↓bladder cancer cell EJ proliferation via (Zhou et al., 2015) polyphenols UBUC T24 and J82 cell) p53/miR-34a axis, ↓mitochondrial image pathway ↑ER oxidative stress. Figure 4. The possible mechanisms of action of pomegranate and onion Quince (Cydonia oblonga) firm fruit flesh (Pacifico et al., 2012). Silva and Hussain Quince (Cydonia oblonga) is the only species in the (2017) conducted many investigations on C. oblonga genus Cydonia, which falls into the Pomoideae sub- Miller (also known as quince) in the past few years. They family of the Rosaceae along with pear and apple. The proved this plant is a low-cost, safe, and good natural yellow fruit may be apple- or pear-shaped and is con- source of various phenolic components, such as flavonol, sidered a bright yellow, a highly astringent, acidulous, flavone heterosides, and caffeoylquinic acids. Efficacy of some plants and herbs in cancer therapy for humans and animals 331 These compounds could provide the active principles 5-O-caffeoylquinic acid was the major component in the of quince leaf and fruit in the treatment of cough, bronchial methanolic extracts of quince. The authors observed that asthma, and hemorrhoids (Oliveira et al., 2007), cystitis quince fruit and leaf extracts revealed clear anticancer (Sezik et al., 2001), constipation, and as a skin emollient properties. This extract has potential anticancer effects (Pieroni et al., 2004). Quince fruit is considered a pivotal on human colon cancer cells (IC50 = 239.7 (43.2 μg/ dietary source of health-promoting molecules due to its an- mL), while no effects on human kidney cells were ob- ti-ulcerative, antibacterial, anti-inflammatory, anti-obesity, served. The anticancer property of peel and pulp extracts and antioxidant properties (Oliveira et al., 2007; Pacifico et was low in the range of extract levels. Therefore, the first al., 2012). The leaf of quince has also been detected to have study revealed that C. oblonga might be helpful as a can- anti-hemolytic activity (Costa et al., 2009), in addition to its cer chemotherapeutic and/or chemopreventive agent. lipid-lowering activities (Pacifico et al., 2012). Quince fruit Alesiani et al. (2010) isolated 59 active compo- extracts have been mentioned to be efficient in inhibiting nents from Cydonia vulgaris peels and categorized allergic ailments. Conclusively, a lipophilic quince extract them based on their spectroscopic features. Among was detected to have skin moisturizing activities. them, five metabolites have been isolated for the first The antiproliferative influence of pulp and peel time such as 3β-linoleoylurs-12-en-28-oic acid, 3β-(18- polyphenolic extracts from C. oblonga fruit on both non- hydroxylinoleoyl)-28-hydroxyurs-12-ene, tiglic acid tumorigenic cells (HEK 293 and NIH 3T3) and human 1-O-β-d-glucopyranoside, 3β-oleoyl-24-hydroxy-24-ethy- colon adenocarcinoma cells (LS174) was studied by lcholesta-5,28(29)-diene, and 6,9-dihydroxymega-stig- Riahi-Chebbi et al. (2015). The same reported that the masta-5,7-dien-3-one 9-O-β-d-gentiobioside. All the pre- highest anticancer activity, without any toxic effect, was vious compounds were tested for their antioxidant and shown by aqueous acetone peel extract (IC50=5 µg/mL), anticancer activity (especially murine B16-F1 melanoma explicitly on LS174 cells. Phenolic ingredients concen- cells). Pacifico et al. (2012) two complex preparations tration in the pulp fraction is one-third lower than in the were in the focus of the present study, i.e., a lipophilic peel. Regarding the phytochemical screening of aqueous quince wax extract (QWE studied two complex prepa- acetone peel, it was found that 13 phenolic compounds rations of quince phytochemicals, i.e., an aqueous fer- are the major active molecules, including rutin, querce- mented one (QAFE) and a lipophilic quince wax extract tin, (−)-catechin, (+)-catechin, isoquercitrin, hyperin, (QWE). The antiproliferative influence against human cryptochlorogenic acid, chlorogenic acid, p-coumaric HeLa, A549, and HepG2 cell lines was investigated. acid, neochlorogenic acid, kaempferol-3-O-glucoside, QAFE was more active than QWE, but sometimes, its kaempferol and kaempferol-3-O-rutinoside (Fattouch influences seemed to be strongly dependent on exposure et al., 2007). Carvalho et al. (2010) studied the phenol- time. Moreover, lipophilic and hydrophilic quince prepa- ic screening and anticancer activity of quince fruit and rations are non-toxic and have health-promoting activi- leaf alongside colon cancer and human kidney cells. The ties. Table 12. Anticancer activities of quince Extract/active ingredient Study type Cancer cell type Mechanisms of action References Methanolic extract from In vitro Human renal (a-498 and 769-p) Many phenolic compounds showed anticancer (Carvalho et al., leaves and fruits and colon (caco-2) effects, such as flavone heterosides, flavonol 2010) cancer cell lines and hydroxycinnamic acid. Lipophilic quince wax In vitro Human Hepg2, A549, and Hela ↑Apoptosis induction (Pacifico et al., extract and an aqueous cell lines ↑Mitochondrial toxicity 2012) fermented Peel (Peph) and pulp poly- In vitro Human colon adenocarcinoma ↑Apoptosis induction (Riahi-Chebbi et phenolic extracts LS174 cells ↑A cell cycle arrest in the G1/S phase, al., 2015) ↑ROS. ↓NF-κB and VEGF. Cydonia vulgaris peels In vitro Murine B16-F1 melanoma cells Antioxidant activities of 3β-linoleoylurs-12- (Alesiani et al., en-28-oic acid, 3β-(18-hydroxylinoleoyl)- 2010) 28-hydroxyurs-12-ene, tiglic acid 1-O-β-d-glucopyranoside, 3β-oleoyl-24- hydroxy-24-ethylcholesta-5,28(29)-diene, and 6,9-dihydroxymegastigmasta-5,7-dien-3-one 9-O-β-d-gentiobioside 332 M.E. Abd El-Hack et al. The development of substitute cancer-specific drugs by an increase in the production of intracellular reactive is essential to overcome tumor resistance. Riahi-Chebbi oxygen species, caspase-independent apoptosis and a cell et al. (2015) studied the antiproliferative effect of pulp cycle arrest in the G1/S phase. Peel extract suppressed and peel (Peph) polyphenolic extracts from the C. oblon- the pro-survival signaling pathway NFκB. It inhibited ga on both no-tumorigenic cells HEK 293 cells and NIH the expression of numerous cellular indicators that were 3T3 fibroblasts and human colon adenocarcinoma LS174 significant in angiogenesis (vascular endothelial growth cells. The Peph extract revealed the strongest anti-cancer factor, VEGF) and cell cycling (cyclin D1). Interestingly, influence, specifically on LS174 cells. On the other hand, the chemotherapeutical agent 5-FU and the combination each Peph phenolic component alone did not show any peel extract exhibited a synergistic inhibitory influence anti-cancer activity, indicating a synergistic influence of on cell viability. Table 12 shows the anticancer activities phenolic compounds. This influence was accompanied of quince. Table 13. Anticancer activities of thyme Extract/active ingredient Study type Cancer cell type Mechanisms of action References Thyme essential oil In vivo PC-3, A-549 and MCF-7 cancer ↓growth in leukemia cells (Esmaeilbeig et Displayed cytotoxic activity alongside MCF- al., 2015) 7, A-549, and PC-3 cancer cells. Thyme essential oil In vivo Oral cavity squamous cell carci- ↓human head and neck squamous cell carci- (Sertel et al., 2011) noma noma (HNSCC) cell growth. Thyme essential oil In vitro Human ovarian adenocarcinoma ↑anticancer activity. (Ismaili et al., IGR-OV1 cell line 2002) Thyme essential oil In vitro Ovarian cancer in vitro cytotoxic activity against tumor cells (Ait M’barek et (carvacrol) resistant to chemotherapy and a significant al., 2007) antitumor effect in mice. Thyme extract In vivo Human lung cancer cell line ↑anti-inflammatory properties by ↓the NF-κB (Oliviero et al., (H460) p65 and NF-κB p52 transcription factors 2016) protein levels followed by ↓pro-inflammatory cytokines (IL-1 beta and IL-8), and Muc5ac secretion in human normal bronchial and tracheal epithelial cells. T. thymol, T. linalool, and In vitro MCF-7 breast cancer cells- HeLa ↓HeLa cervical cancer and MCF-7 breast (Deering et al., T. thujanol. cervical cancer cancer cell viability by approximately 20% 2017) after 24 hours. Figure 5. The possible mechanisms of action of thyme, quince and indigo Efficacy of some plants and herbs in cancer therapy for humans and animals 333 Thyme (Thymus vulgaris) data a vailability statement Thyme (Thymus vulgaris L.) is a Mediterranean aro- No data are available. matic herb. T. vulgaris is the most common variety. It is acknowledgment commonly used for ornamental, culinary, and medicinal The authors thank the Deanship of Scientific Re- purposes (De Martino et al., 2009). Thyme preparations search at Shaqra University for supporting this work. are widely used in dried herbs, liquid extracts, tinctures, or elixirs. These thyme preparations’ different effects should be carefully considered in their chemical composition. references Thymol, carvacrol, eugenol, tannins, saponins, and luteolin are all active agents in thyme (Kluth et al., 2007). Most of Abd El-Hack M.E., Alagawany M., Farag M.R., Tiwari R., Karthik the pharmacological effects of thyme are attributed to the K., Dhama K. (2016). Nutritional, healthical and therapeutic ef- ficacy of black cumin (Nigella sativa) in animals, poultry and hu - presence of active agents carvacrol and thymol, the main mans. Int. J. 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Wang X., Bai H., Zhang X., Liu J., Cao P., Liao N., Zhang W., Wang Received: 3 X 2022 Z., Hai C. (2013). Inhibitory effect of oleanolic acid on hepato- Accepted: 21 X 2022

Journal

Annals of Animal Sciencede Gruyter

Published: Apr 1, 2023

Keywords: herbs; plants; anticancer; tumor; therapy; natural remedies

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