Anti-cancer potential of South Asian plants

Phyto-chemicals are increasingly being used in the treatment of cancer because of their availability, potential anti-cancer activity with less adverse effects when compared with chemotherapy. The variation of climate and geography in South Asian countries provides a nursing environment for the growth of versatile plant species, that are repeatedly drawing attention of the scientific community. In this review, we have focused on the anti-cancer potential of thirty plants, which are commonly found in Bangladesh, India, Nepal, Pakistan and Sri Lanka, with their mechanisms of action. In particular, we have discussed the bio-active components that display anti-cancer activity, which have been identified in these plants. This review may help researchers to profile plants with known anti-cancer effect of this region and further investigations of anti-cancer agents in medicinal plants from South Asia.


Phyto-chemicals, as Anti-cancer Agents
In the last century, significant development in bio-medical science has conquered many diseases, however cancer remains ambiguous especially from a therapeutic perspective. Cancer is still a growing health problem world-wide, and it is the second most common cause of death from disease after myocardial infarction. Tumor or neoplasm is usually defined as a growth of an abnormal mass of tissue due to uncontrolled cellular growth, while cancer is the term of all malignant tumors 1 . Non-lethal genetic damage by multi-step carcinogenesis allows for the neoplastic transformations, such as selfsufficiency in growth signal, insensitivity to growth-inhibitory signal, evasion of apoptosis, limitless replication, sustained angiogenesis and the ability to invade and metastasize 2 . However, cancer to some degree is a preventable disease, as cancer risk can be reduced by avoidance of cancer-causing biological, chemical, and physical agents, in addition to the habitual consumption of cancer protective foods 3 . Current research emphasis focuses on synthetic chemotherapeutic drugs but unfortunately conventional chemotherapy with synthetic drugs evoke severe side effects.
There are thousands of scientific studies that have focused on the pharmacological activity of bio-active components from plants, increasing interest from scientific community as cancers suppressant. Biological targets of phyto-chemicals in mammalian cells were found to be involved in inflammatory processes and oncogenic transformation, such as the alteration of cell cycle control, apoptosis evasion, angiogenesis and metastases 4 . Additionally, epidemiological studies suggest that the daily intake of certain phyto-chemicals can reduce the incidence of several types of cancers 5 . Thus, chemoprevention by dietary phyto-chemicals alone immerges as one of the most promising approaches for reduced risk of cancer development. On the other hand, phyto-chemicals act in synergy with chemotherapeutic drugs to overcome cancer cell drug resistance, and further application of specific phyto-chemicals may also allow the use of lower concentrations of drugs in cancer treatment with an increased efficacy 6 . Interestingly, according to WHO, approximately 80% of the world's inhabitants rely on traditional plant derived medicine for their primary health care 7 . Investigation of the underlying pharmacokinetic mechanisms through which phyto-chemicals evoke their anti-cancer effect introduces a panel of molecular targets. This panel includes apoptotic proteins (i.e. caspases, bax etc), protein kinases (i.e., PKA, PKC, MAPK, TYK2 etc), anti-apoptotic proteins (i.e., bcl2, TRAF1, Survivin etc), Growth factors (i.e., TNF, EGF, FGF, PDGF etc), transcription factors (i.e., Ap1, NF-κB, Nrf2, p53 etc), cell adhesion molecules (i.e., ICAM-1, VCAM etc) and cell cycle proteins (i.e., Cyclin D, CDK1, CDK2, p27, p21 etc). Moreover, phyto-chemicals interfere with multiple cellsignaling pathways 8 . A schematic diagram of the common anti-cancer mechanisms of phyto-chemicals has been depicted in Figure 1.
In South Asia, the extraordinary variation in climate and geography provides a vast spectrum of environmental conditions for the growth of versatile plant species, that are repeatedly drawing attention from the scientific community. In *To whom correspondence should be addressed. E-mail: asadkhanbmj@yahoo.com this review, we have focused on the anti-cancer potential of certain herbal plant species which are commonly grown in South Asian countries such as, Bangladesh, India, Nepal, Pakistan and Sri Lanka. We have searched databases such as Pubmed, Google Scholar, Hinari and AGORA for the basic and clinical research publications relating to the anti-cancer effects of these plants. In this review, we have included only those plants, which are commonly found in a broad spectrum range of South Asia, and excluded plant species, which have narrow spectrum of habitat.

South Asian Plants with Anti-cancer Activities
Different species of plants from South Asian countries have been reported to have anti-cancer potential ( Table 1). Some of these plants are endemic world-wide, while some are strictly native. Multi-step carcinogenesis through cancer-causing agents propels normal cells to divide uncontrollably by apoptosis evasion. The ultimate result is the neoplastic transformation of normal cells. Additional tumor progression through clonal proliferation, immune evasion and angiogenesis leads non-metastatic tumor that usually metastasizes to a secondary site after the loss of adhesiveness and diversification. Preventive and anti-mutagenic phyto-chemicals halt or retard the progression of normal and precancerous cells respectively into malignant, or reverse the promotion stage of multi-step carcinogenesis. Anti-proliferative phyto-chemicals inhibit cell growth and proliferation while apoptosis inducer phyto-chemicals induce apoptosis of neoplastic cells. Another pronounced impact of phyto-chemicals is the prevention of metastasis and angiogenesis 2,3,8 .

Abrus precatorius L.:
Abrus precatorius L. is a deciduous dextrose climber with slender flexible branches. It is commonly known as 'Indian liquorice' and belongs to the Fabaceae family. A. precatorius is known in local languages as 'Kunch' in Bangladesh, 'Guncha' in India, 'Olida' in Sri Lanka, 'Ratigedi' in Nepal and 'Ghunchchi Surkh' in Pakistan. The early finding of anti-cancer activity of A. precatorius comes from the study by Reddy and Sirsi 9 . They identified a protein, isolated from the seeds of A. precatorius, which exhibited anti-tumor activity against Yoshida sarcoma in rats and fibrosarcoma in mice. They also observed an association of the anti-tumor activity with a cytotoxic effect on the tumor cells 9 . In a short term toxicity study using Dalton's lymphoma ascities (DLA) cells, A. precatorius seed extracts showed antitumor activity. The crude extract of A. precatorius seeds and its fractions also displayed cytotoxicity against small cell lung carcinoma (A549 cell line) 10 . Two varieties of this toxic protein (Abrin-a, and Abrin-b) were purified from the seeds of A. precatorius, which were similar but not identical 11 . Interestingly, Abrin-a, and Abrin-b agglutinated Sarcoma 180 cells and Ehrlich ascites tumor cells in vitro. It was postulated that Abrin-a, and Abrin-b might have ameliorate immune responses towards target cells through agglutination associated anti-body response. Moreover, both of these two proteins could have inhibited the growth of Ehrlich ascites tumor cells at a sub-lethal dose when tumor cells were injected simultaneously with these proteins in vivo 11 .

Alangium salviifolium Wang.: Alangium salviifolium
Wang. is a deciduous, rambling shrub or a tree belonging to the family Alangiaceae. 'Sage-leaved alangium' is the common name of A. salviifolium, and it is locally known as Ankor Kanta (Bangladesh), Angol (India) and Ruk anguna (Sri Lanka). Reports propose its use as an anti-diabetic, antiepileptic, analgesic and anti-inflammatory, in particular the activities of the polar (chloroform-, ethanol-, and aqueous-) extracts of A. salvifolium seeds 16 . Chloroform extract of A. salvifolium flower displays anti-tumor effect against Ehrlich ascites carcinoma (EAC) in mice 17 . Intra-peritonial administration of the non-polar extracts of A. salvifolium flower at a dose of 10 mg/Kg, mimicked the anti-cancer activity of bleomycine in EAC bearing mice 18 . Biologically active ingredients of A. salvifolium include flavinoids, glycosides, alkaloids and saponins 19,20 . Nine protoberberine alkaloids have been isolated from A. salviifolium, among which, 27-O-trans-caffeoylcylicodiscic acid (3) and myriceric acid B (4) exhibited cytotoxic activity towards the MOLT-3 cell line, while 3-O-demethyl-2-O-methylalangiside (5) selectively inhibited the growth of the HepG2 cancer cell line 21 .

Amoora rohituka Roxb.: Amoora rohituka
Roxb., is a species of the Meliaceae family, and commonly known as 'Rohituka'. It is locally known as 'Royna' in Bangladesh, and 'Harin-hara' in India. Both in vivo and in vitro investigation flourished the anti-cancer effect of A. rohituka. Organic solvent extracts of A. rohituka bark have been reported to have significant anti-tumor activity against DLA and EAC in mice, and further its selective cytotoxic activity against breast cancer cell line MCF-7 and DLA cells 22,23 . Amooranin, a triterpenic acid extracted from the bark of A. rohituka trees, has significant anti-cancer potential against N-nitrosomethyl ureainduced mammary adenocarcinoma in rats and SW620 human colon carcinoma xenograft in mice 24 . The cytotoxicity of Amooranin against a panel of cancerous cell line including human mammary carcinoma MCF-7, breast carcinoma MDA-468, multi-drug resistant breast carcinoma MCF-7/TH, multidrug-resistant leukemia (CEM/VLB), colon carcinoma (SW620/Ad-300) provides an insight to the possible mode action of A. rohituka. Cell cycle arrest at G2/M phase and induction of apoptosis via caspase activation pathway are likely to contribute to the cytotoxicity of amooranin 25,26 . Furthermore, flavopiridol (6) is a novel semi-synthetic flavone analogue of rohitukine (7), chromone alkaloid isolated from an A. rohituka, that possess significant anti-cancer activity against non-Hodgkin's lymphoma, renal, prostrate, colon, and gastric cancers. It inhibits the tumor growth via cyclin-dependent kinases (CDK2 and CDK1) inhibition and inducing apoptosis in cancerous cells 27 . Therefore, rohitukine might have similar or partial mechanism to exert its anti-cancer effects of A. rohituka.

2.7
Calotropis procera: Calotropis procera, an erect shrub, commonly known as 'Apple of Sodom'. It is a species of flowering plant in the Asclepiadaceae family, and locally known as Akanda (Bangladesh), Akado (India), Wara (Sri Lanka). The organic extracts of stems C. procera have been reported to have cytotoxicity against human leukemia cell line HL-60, human colon cancer cell line HCT-8 and murine melanoma cell line B-16/F10. Stem organic extracts also possess anti-tumor activity against mice bearing Sarcoma 180 tumors 35 . The chemopreventive effects of C. procera latex is reported through the inhibition of different mediators of inflammation with selective cytotoxicity independent of intrinsic pathway of apoptosis against hepatocellular carcinoma in the X15-myc transgenic mouse model 36 . To reveal the probable phyto-chemicals responsible for anti-cancer effect, focus has been directed towards heat-stable latex proteins from C. procera due to its inhibitory activities on sarcoma 180 growth 37 . On the other hand, studies have also emphasized non-protein phyto-constituent such as the cardiotonic steroid UNBS1450 (8) from C. procera that additionally exert anticancer activity by cytoskeleton disorganization, autophagyrelated cell death induction, NF-κB activation repression as well as c-Myc down-regulation in cancer cells 38 .

2.9
Dendrophthoe falcata (L.F.) Ettingsh: Dendrophthoe falcata is a perennial, climbing, woody parasitic plant of the family Loranthaceae. The common name of D. falcata is 'Honey Suckled Mistletoe' but is locally known as Delum pilia (Sri Lanka) and Bajrangi (Bangladesh) etc. D. falcate imparts anti-cancer activity as evidenced in cancer cell lines and animal models. Ethanolic and aqueous extracts from the stem of D. falcata possess high cytotoxic activities against human breast cancer cells (MCF-7) 43 . Ethanol extract of D. falcate displayed potent anti-cancer activity against EAC-bearing mice. This anti-cancer activity was found similar to that of cisplatin 44 . Hydroalcoholic extract of D. falcata showed a protective role against DMBA (7,12dimethylbenz(a)anthracite)-induced breast carcinogenesis with a concomitant amelioration of antioxidant status. Thus, antioxidant activity of D. falcata extract might partially contribute to the observed anti-cancer activity, in addition to the cytotoxic effect 45 . The phyto-chemical constituents of different part of D. falcate include flavonoids (quercetrin, catechin) tannins (gallic acid, chebulinic acid) oleonolic acid, β-amyrin-0-acetate, leucocynidin and sterols (β-sitosterol and stigmasterol) some of which have been documented as anticancer components 46 .

2.10
Dioscorea bulbifera L.: Dioscorea bulbifera L. belongs to the Dioscoreaceae family and commonly known as 'Air potato'. Its local names are Lota-bori (Bangladesh), Karukanda (India), Zaminek (Pakistan), and Udala (Sri Lanka). D. bulbifera rhizome is used for treatment of leprosy and tumors in Bangladesh within an ethno-botanic frame 47 . Investigations showed anti-cancer activity of D. bulbifera in several cancers. Various impacts at the molecular level were observed regarding different D. bulbifera organic extracts treatment. Petroleum ether fraction of D. bulbifera showed potential effect against HepA with microstructure abnormality of HepA cells surface 48 . Cui 49 reported the modulation of immune response and induction of apoptosis by crude polysaccharides of D. bulbifera against cervical carcinoma in U14bearing mice. Immune system modulation might be related to anti-tumor effects of D. bulbifera, as reported in S180 and H22 tumor cells bearing mice 50 . Several phyto-chemicals isolated from D. bulbifera are considered as active principle for anti-cancer activity, including kaempferol-3, 5-dimethyl ether, caryatin, (L)-catechin, myricetin, quercetin-3-Ogalactopyranoside, myricetin-3-O-galactopyranoside, myricetin-3-O-glucopyranoside and diosbulbin B 51 .

2.11
Embelia ribes Burm. F.: Embelia ribes Burm. F. is commonly known as 'False black pepper', and belongs to the Myrsinaceae family. It is locally known as Biranga (Bangladesh), Bidang (India), Walangasa (Sri Lanka), and Baobadang (Pakistan). A methanol extract of E. ribes fruits showed protective effect against multi-mutagenicity and genotoxicity, induced by cyclophosphamide in mice, as multi-mutagenicty is considered as a molecular basis of cancer 52 . E. ribes contains embelin, quercitol (polyphenols), flavonoids, tannins, saponins and alkaloid 53,54 . Embelin (EB), a phenolic compound, is protective against diethylnitrosamine/phenobarbital induced hepatocarcinogenesis in rat 55 . Embelin also has the capacity to protect against acetic acid induced ulcerative colitis in rats 56 . This compound exerts its anti-cancer activity by cytotoxicity toward cancer cells through the induction of apoptosis, characterized by the accumulation of cells in the sub G1 phase, positive annexin-V binding, down-regulation of anti-apoptotic (Bcl-2, Bcl-xL, survivin, IAP-1, and IAP-2) and proliferative (cyclin D1) proteins, activation of caspase-3, and cleavage of PARP 56 .

Ficus benghalensis L.:
Ficus benghalensis L. is commonly known as 'Indian Banyan'. It is locally known as Bot (Bangladesh), Bargad (India), Gotu Nuga (Sri Lanka), and belongs to the family Moraceae. Although there was immunomodulatory activity demonstrated using a methanol extract of F. benghalensis roots in an animal model 57 , only an in vitro study exists in support of its anti-tumor activity of this plant. Hawary et al. 58 reported the methanol extract of F. benghalensis as a weak anti-tumor agent against HepG2 and MCF-7 tumor cell lines at a lower extant. However, this report might not represent the actual anti-cancer potential of F. benghalensis as suggested by the phyto-chemical constituent make up of F. benghalensis. Phyto-chemical analysis revealed the presence of several potential anti-cancer agents in different parts of plants especially in the leaves (i.e., lupeol, psoralen and β-sisterol) 59-62 .

2.13
Ficus religiosa L.: Ficus religiosa L. is commonly known as 'Bo-tree', and belongs to the Moraceae family. It is locally known as Pan Bot (Bangladesh), Pipli (India), Bo (Sri Lanka) and Pippal (Pakistan). In a study, methanol and water extract of F. religiosa exhibited cyto-toxicity activity against HT29 and MDA-MB-435S cancer cells 12 , but with more selective fractionation, the anti-cancer effect was increased in efficiency, as reported in a MCF-7 cell line 63 . F. religiosa contains a wide range of phyto-chemicals like phenols, amino acids, fatty acids, tannins, steroids, alkaloids and flavonoids are distributed throughout the different parts of plant. However, the anti-cancer activity specifically focuses on the several phyto-constituents including flavonols i.e. quercetin and myricetin, and phytosterols namely stigmasterol and βsitosterol 64 .

2.15
Jatropha gossypiifolia L.: Jatropha gossypiifolia is a bushy gregarious shrub belonging to the Euphorbiaceae Family and commonly known as 'Bellyache Bush'. It is locally known as Lal Bheranda (Bangladesh), Bhenenda (India), Rathu Erandu (Sri Lanka). Beyond the ethno-botanic use as an anti-cancer plant, there exist no direct evidence of anti-cancer activity of the crude extract of J. gossypiifolia, but phyto-chemicals of J. gossypiifolia have been examined and are promising as anticancer agents. The reported phyto-chemical constituents include lignans and several diterpenoids, such as falodone (9) and jatrophone (10) 68,69 . Falodone has potent proliferation inhibitory activity in A-549 human cancer cell line 70 , while Jatrophone exhibits anti-cancerous properties against P338 lymphocytic leukemia 71 .

Kaempferia parviflora Wall.: Kaempferia parviflora
Wall. Baker is a stemless, small, rhizomatous herb, commonly known as 'Thai Ginseng'. It is a member of the ginger family (Zingiberaceae), and is locally known as 'Kalahalood'. The ethanolic extract of K. parviflora rhizome is effective in suppressing the growth of HL-60 human leukemic cells 72 . This effect was found to be associated with the hallmarks of apoptotic cell death i.e., morphological cell change, loss in mitochondrial transmembrane potential and activation of caspase. Similar effect was observed using the crude ethanol extract of K. parviflora as reported in cholangio-carcinoma cell lines HuCCA-1 and RMCCA-1, where 5,7,4′trimethoxyflavone (11) was identified as the anti-cancer bioactive component 73 . Moreover, 3,5,7,4′tetramethoxyflavone, 5,7,4′-trimethoxyflavone and 5-hydroxy-3,7,3′,4′-tetramethoxyflavone purified from its rhizome extracts induces cytoxicity in human colorectal carcinoma (HCT-15) cells 74 .  known as 'Spanish Flag'. The local name of L. camara is 'Urusia' in Bangladesh, 'Caturang' in India, and 'Gandapata' in Sri Lanka. Initally, the toxicity of L. camera in some animal species drew the attention of scientists, who revealed its anticancer effect 75 . Mahato et al. 76 isolated a novel flavonol glycoside, named camaraside (12), an anti-tumor agent from L. camera 76 . In addition, Sharma et al. 77 showed that lantadene A (13), a torpedoed component of L. camera, induced concentration and time-dependent inhibition of HL-60 cell proliferation by cell cycle arrest in the G0/G1 phase. Lantadene A also induced efficient HL-60 cell apoptosis by activating the caspase-3 pathway, and via the down-and up-regulation of Bcl-2 and Bax expression respectively 77 .

Mollugo pentaphylla Linn.: Mollugo pentaphylla
Linn., a perennial herb, is a member of Molluginaceae family that is commonly known as 'Itch Flower'. Its local names include 'Khetpapra (Bangladesh), and Jaraasi (India). In chemically induced model of carcinogenesis (DMBA is used as a carcinogen and TPA as a tumor initiator), methanol extract of M. pentaphylla showed significant anti-tumor activity 81 . As an ingredient of Peh-Hue-Juwa-Chi-Cao, traditional Chinese medicine preparations, M. pentaphylla exhibited anti-tumor activity against sarcoma-180 cells implanted subcutaneous tumors 82 . Several phyto-chemicals isolated from this plant include flavones such as apigenin and mollupentin, triterpenoids such as mollugogenol A, mollugogenol B, mollugogenol D, oleanolic acid and a steroid β-sitosterol 83 , among which, apigenin, oleanolic acid, β-sitosterol have been implicated to possess an anti-cancer potential.

2.20
Murraya koenigii Linn.: Murraya koenigii Linn., is a plant belonging to the Rutaceae family and commonly known as 'Curry leaf tree'. The local name of M. koenigii are Bar Sunga (Bangladesh), Mitha neem (India), and Karapincha (Sri Lanka). Muthumani et al. 84 found that the non-polar extract of M. koenigii caused potent cytotoxic effect during short-term incubation (for 3 hours) in DAL cells. They have demonstrated that M. koenigii significantly decreases the viability and growth of DAL cells, when injected intraperitoneally into the mice, which was comparable to the effect of 5-flurouracil 84 . The alkaloids mahanine (16), mahanimbicine (17) and mahanimbine (18) were isolated from M. koenigii, and showed a significant anti-tumor activity against MCF-7, HeLa and P388 cell lines 85 . Mahanine induces the death receptormediated extrinsic pathway of apoptosis in MOLT-3 cancer cells, while also inducing the mitochondria dependent intrinsic pathway of apoptosis in HL-60 86,87 . Furthermore, 34 essential oils have been isolated from the leaves of M. koenigii, and all of which showed potent anti-bacteria and cytotoxic effects in a dose dependent trend 85 . These essential oil included 12 oxygenated monoterpenes, 12 sesquiterpene hydrocarbons, nine oxygenated sesquiterpenes and one oxygenated diterpene.

2.21
Nelumbo nucifera Willd.: The plant Nelumbo nucifera Willd., belongs to the family Nelumbonaceae, and popularly known as 'Sacred Lotus'. It is locally known as Kamal (India), Nelum (Sri Lanka), Nilufer (Pakistan) and and Padam (Bangladesh). During an in vivo study using the hydroethanolic extract of N. nucifera, there was noticable inhibition of growth and also the survival in mice who were intraperitonealy injected EAC cells, by modulating lipid peroxidation and augmenting antioxidant defense systems in EAC bearing mice 88 . Hemanth et al. 89 reported a similar effect of acetone extract of N. nucifera leaves in EAC bearing animals, and a significant cytotoxicity against HBL-100 in vitro. Also, the methanol extracts exhibited significant anti-proliferative effect in Calu-6 human pulmonary carcinoma and SMU-601 human gastric carcinoma cells 89 . Repeated reports confirm that the major constituents present in the N. nucifera are alkaloids (liensinine, neferine, pronuciferine, isoliensinine, negferine, asimilobine, nuciferine, remrefidine, isoliensinine etc.) and flavonoids, glycosylated flavonols, flavonol, aglycones (myricetin, quercetin, leucocyanidin, rutin, kaempferol, isorhamnetin, astragalin etc.) 90,91 . Neferine (19), a major alkaloid component in N. nucifera embryos, possessed a potent growthinhibitory effect in human osteosarcoma cells, with a mechanism of p21-dependent cell cycle arrest at G1 due to p38 MAPK-mediated p21-stabilizing effect of neferine 91 .

2.23
Oxalis corniculata Linn.: Oxalis corniculata Linn., is a small creeping, low growing herbaceous plant, and is a member of the Oxalidaceae family, commonly known as 'Indian Sorrel'. It is locally known as Amrul (Bangladesh), Tipatia (India), Embul embiliya (Sri Lanka), Khatt-i-buti (Pakistan). The ethanolic extract of O. corniculata was found effective in inhibiting the tumor growth in EAC inoculated mice 96 .

2.24
Physalis minima L.: Physalis minima L., a perennial herb which belongs to the Solanaceae family, and is commonly known as the 'Sun Berry''. It is locally known as Potka (Bangladesh) and Bandapariya (India). Studies repeatedly pronounced the striking anti-cancer effect of P. minima against several cancer cell lines. The chloroform extract of P. minima produced a significant growth inhibition in human T-47D breast carcinoma cell death via p53, caspase-3, and c-myc-dependent apoptotic pathways 97 . A combined effect of apoptotic and autophagic programmed cell death was found by chloroform extract of P. minima in cytotoxicity against Caov-3 cells 98 . The induction of this programmed cell death was mediated via c-myc, p53 and caspase-3 dependent pathway. The chloroform extract of P. minima also exhibited remarkable cytotoxic activities in NCI-H23 human lung adenocarcinoma cell line via apoptotic cell death 99

2.27
Solanum nigrum Linn.: Solanum nigrum Linn. belongs to the Solanaceae family, and commonly known as Black Nightshade. It is locally known as Kack-machi (Bangladesh), Bandakh (India), Kalu Kamberiya (Sri Lanka), and Ab Makoh (Pakistan). Extracts from S. nigrum was found to induce a strong cytotoxic effect in HepG2 hepatoma cells and AU565 breast cancer cells by inducing apoptosis and/or autophagocytosis 106,107 . Actually, a low dose treatment induced only autophagy, while high dose treatment induced both of autophagy and apoptosis. Although various parts of the S. nigrum plant contain polyphenols, gentisic acid, luteolin, apigenin, kaempferol, m-coumaric acid, anthocyanidin, their role in apoptosis is not clear. The crude polysaccharides from S. nigrum concomitantly up-regulates pro-appototic gene Bax and down-regulates Bcl-2 and mutant p53 gene expression in mice bearing cervical cancer (U14) 108 . On the other hand, pepsin and pancreatin digestion resistant peptide Lunasin has been claimed as a bioactive and bioavailable component due to inhibition of H3 and H4 acetylation and the phosphorylation of the Rb protein in mammalian cells and in a skin cancer mouse model 109 .

Tinospora crispa:
Tinospora crispa is an indigenous climber plant that is locally known as Akar Patawali in Bangladesh and Geta Kinda in Sri Lanka. It is a member of the Menispermaceae family. Several studies suggested the efficient cytoxicity of T. crispa polar extracts. Aqueous crude extract of T. crispa was treated against MCF-7, HeLa, HepG2 and Caov-3 cancer cell lines, using cisplatin and tamoxifen as standard in a study by Zulkhairi et al. 110 . The extract exhibited anti-proliferative activity in all cancer cell lines, which was comparable with standard drugs 110 . Ibahim et al. 111 also treated several cancer cell lines (MCF-7, MDA-MB-231, HeLa and 3T3) with water, methanol or chloroform extract of T. crispa stem, and reported a dose-dependent anti-proliferative activity against all cancerous cell lines with the most potent effect of methanol extract on MDA-MB-231 and MCF-7 111 . The antiproliferative effect of T. crispa might be due to its chemical substances especially alkaloids, which are known to have anti-cancer properties. Several alkaloids have been isolated, namely tinoscorside A (26), N-formylanonaine (27), N-formyldehydroanonaine (28), N-formylnomuciferine (29), N-demethyl-N-formyldehydronornuciferine (30), magnoflorine (31), paprazine (32), N-trans-feruloyltyramine (33), Nformylasimilobine 2-O-β-D-glucopyranoside (34) from T. crispa 112 .

2.29
Tragia involucrate L.: Tragia involucrata L. is a member of the Euphorbiaceae family, and commonly known as 'Stinging Nettle'. It is locally known as Bichuti (Bangladesh), Barhanta (India), Wel Kahambiliya (Sri Lanka). T. involucrate was found to have anti-cancer activity both in vitro and in vivo model system. The hexane and ethyl acetate extracts of T. involucrata significantly increased the life span of EAC baring mice in a dose dependant manner 113 . Phytochemical analysis of T. involucrata showed the presence of flavonoids and terpenoids that were claimed to have possess anti-cancer activity, and probably explain the cytotoxic effect of T. involucrate extract 114 .

Concluding Remarks
The actual contribution of South Asia toward the anticancer research seems to be deemed and negligible. Being third world countries, research facilities are limited, whereas natural resourses are abundant. The variation in geography and environment of this region provides a rich plant biodiversity, many of which can be used as the source of anti-cancer agents. As the use of phyto-chemicals in cancer treatment is promising and increasing rapidly, the proper scientific study to extract chemicals, investigation of their anti-cancer role in details, and clinical studies might be the interesting subject of future cancer research.
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