INTRODUCTION:

A neoplasm is an abnormal mass of cells that exhibits uncontrolled proliferation and persists after cessation of the stimulus. In general, neoplasms are irreversible, and their growth is autonomous. In contrast to benign tumors, malignant neoplasms or cancers (epithelial cell origin) have the added property of invading contiguous tissues and metastasizing to distant organs, where subpopulations of neoplastic (malignant) cells take up residence, grow, and invade again. Therefore, cancer is an uncontrolled proliferation of abnormal cells and causes death. Cancer is now a major worldwide disease, accounted for over 7 million deaths per year. The incidence of neoplastic disease increases with aging. In developing countries, some types of cancer in certain organs show high incidence^l. However, in developed countries, with the aging of population and decrease in the mortality rate from cardiovascular diseases, cancer is one of the major leading causes of death^2,3. Considering the progress in the methods of cancer detection and treatment, we are still facing a number of problems. For instance, difficulty in the early diagnosis of certain types of cancer. These types of cancer include primary cancers in pancreas, gall bladder, lung (small cell carcinoma), stomach (scirrhous type of adenocarcinoma), testis and prostate (occult or latent neoplasms).

Another problem is the presence of second primary tumors in patients who had previously been cured of their first cancer by adequate treatment. These groups of patients are now increasing in Japan ⁴.

In general, prevention of a disease is the best approach to its control. To this end, there are proposal cancer preventive methods. These methods are divided into primary, secondary (early detection and therapy of cancer), and tertiary (therapy or prevention overt cancer and its recurrence and metastasis) prevention. The primary prevention has basically avoided the cancer development. It includes: (a) elimination of known carcinogens and (b) desirable alterations in nutrition. Clearly, one of the top priorities in cancer prevention is the elimination of known carcinogens, such as tobacco⁵. Occupational cancers should also be eliminated. Until recently, early detection of precancerous and cancerous lesions and the elimination of carcinogenic agents dominated the field of cancer prevention. However, complete elimination of carcinogens is not likely to be socially-acceptable or achievable. Cancer therapy, which includes surgical intervention, radiotherapy and chemotherapy, has proved highly efficacious with diseases such as acute lymphoid leukaemia of childhood but is, as yet, less successful with many other forms of cancer. Cancer diagnosis and cancer therapy can be traumatic for the patient. Hence, other strategies must also be developed and applied.

Plants have a long history of use in the treatment of cancer. Hartwell lists more than 3000 plant species that have reportedly been used in the treatment of cancer, but in many instances, the “cancer” is undefined, or reference is made to conditions such as “hard swellings”, abscesses, calluses, corns, warts, polyps, or tumors, to name a few ⁶. Such symptoms would generally apply to skin, “tangible”, or visible conditions, and may indeed sometimes correspond to a cancerous condition, but many of the claims for efficacy should be viewed with some skepticism because cancer, as a specific disease entity, is likely to be poorly defined in terms of folklore and traditional medicine. This is in contrast to other plant-based therapies used in traditional medicine for the treatment of afflictions such as malaria and pain, which are more easily defined, and where the diseases are often prevalent in the regions where traditional medicine systems are extensively used. Nevertheless, despite these observations, plants have played an important role as a source of effective anticancer agents, and it is significant that over 60% of currently used anti-cancer agents are derived in one way or another from natural sources, including plants, marine organisms and micro-organisms ^7,8.

The search for anti-cancer agents from plant sources started in earnest in the 1950s with the discovery and development of the vinca alkaloids, vinblastine and vincristine, and the isolation of the cytotoxic podophyllotoxins. As a result, the United States National Cancer Institute (NCI) initiated an extensive plant collection program in 1960, focused mainly in temperate regions. This led to the discovery of many novel chemotypes showing a range of cytotoxic activities ⁹, including the taxanes and camptothecins, but their development into clinically active agents spanned a period of some 30 years, from the early 1960s to the 1990s. This plant collection program was terminated in 1982, but the development of new screening technologies led to the revival of collections of plants and other organisms in 1986, with a focus on the tropical and sub-tropical regions of the world. It is interesting to note, however that no new plant derived clinical anti-cancer agents have, as yet, reached the stage of general use, but a number of agents are in preclinical development.

Medicinal plants possess immunomodulatory and antioxidant properties, leading to anticancer activities. They are known to have versatile immunomodulatory activity by stimulating both non-specific and specific immunity ^{8, 10}. Plants contain several phytochemicals, which possess strong antioxidant activities. The antioxidants may prevent and cure cancer and other diseases by protecting the cells from damage caused by ‘free radicals’ – the highly reactive oxygen compounds. Thus consuming a diet rich in antioxidant plant foods (e.g. fruits and vegetables) will provide a milieu of phytochemicals, non-nutritive substances in plants that possess health protective effects. Many naturally occurring substances present in the human diet have been identified as potential chemopreventive agents; and consuming relatively large amounts of vegetables and fruits can prevent the development of cancer ^{2, 11}. Compared with meat eaters, most, but not all, studies have found that vegetarians are less likely to be diagnosed with cancer. Vegetarians have also been shown to have stronger immune function, possibly explaining why they may be partially protected against cancer ^{12, 13}. Many plant-derived products have been reported to exhibit potent antitumor activity against several rodent and human cancer cell lines.

DRUGS IN CLINICAL USE AND STUDY:

Vinca Alkaloids:

History and Chemistry:

The history of the Vinca alkaloids and the story of their discovery are well known ^{14, 15}. Because of a folklore that had developed about the oral hypoglycaemic properties of extracts of the periwinkle plant, they were studied independently by two different laboratories. The plants had no antidiabetic actions but were shown to cause granulocytopenia and bone marrow depression in rats, and were subsequently found to prolong the life of mice bearing a transplantable lymphocytic leukaemia. The investigators quickly saw the possibilities and began vigorous development of these agents, and in a relatively short time VCR and VLB were isolated and put into clinical trial ¹⁶.

The chemistry of the Vinca alkaloids has been reviewed extensively ¹ ⁷. These agents are derived from the periwinkle plant, Catharanthus roseus G. Don (frequently known as Vinca rosea Linn). The Vinca alkaloids are dimeric compounds in which indole and dihydroindole nuclei are joined together with other complex ring systems. Modifications have been made on both the velbanamine (catharanthine) and vindoline moieties ¹⁷. Note that VCR and VLB differ only in the presence of a formyl or methyl group, respectively, in the vindoline moiety. As will be seen later, this apparently modest difference in structure, which does not alter in any fundamental way the mechanism of action of and binding to tubulin, is of considerable significance with regard to the clinical spectrum of antitumor efficacy and clinical toxicity of these drugs. The molecular alterations in VRLB differ from those of other Vinca alkaloids: although the vindoline moiety of VLRB is the same as that of VLB, the catharanthine moiety has been changed, with an 8-membered ring replacing the hydroxyl and 9-membered ring; as a consequence, the overall lipophilicity of VLRB is significantly increased compared to the other Vinca alkaloids.

Mechanism of Action:

Among the many biochemical effects seen after exposure of cells and tissues to the Vinca alkaloids are disruption of microtubules, inhibition of synthesis of proteins and nucleic acids, elevation of oxidized glutathione, alteration of lipid metabolism and the lipid content of membranes, elevation of cyclic adenosine monophosphate (cAMP), and inhibition of calcium-calmodulin–regulated cAMP phosphodiesterase ¹⁸. The Vinca alkaloids are relatively hydrophobic molecules that partition into lipid bilayers in the uncharged state, altering the structure and function of membranes ¹⁹. Of their diverse effects, their only well-documented direct action is disruption of microtubules, which results from their reversible binding to tubulin, the subunit protein of microtubules. At pharmacologically active concentrations, most of the biochemical effects associated with exposure to the Vinca alkaloids are probably secondary to disruption of microtubules, although it is possible that drug-induced changes in lipid bilayers may alter some membrane-dependent processes. At high intracellular concentrations, these compounds induce formation of large crystalline aggregates that are composed of tubulin and drug ²⁰. Despite their many biochemical actions, the antineoplastic activity of the Vinca alkaloids is usually attributed to their ability to disrupt microtubules, causing dissolution of mitotic spindles and metaphase arrest in dividing cells).^14,21. However, disruption of microtubules also leads to toxicity in nonmitotic neoplastic cells, and although the Vinca alkaloids are classified as mitotic inhibitors, their antineoplastic activity in the clinical treatment of cancer probably arises from perturbation of a variety of microtubule-dependent processes, as well as from disruption of the cell cycle and induction of programmed cell death ²².

Taxanes: Paclitaxel (Taxol) and Docetaxel (Taxotere):

Much effort has gone into the chemistry and clinical trials of the taxanes. These agents, typified by paclitaxel and the semi synthetic analogue, Taxotere (docetaxel), have been the subject of intense clinical scrutiny, and their chemistry, biochemical actions, pharmacology, and clinical activities are the subject of several recent excellent reviews and monographs ^23-26.

History and Chemistry:

Paclitaxel was isolated in 1971 from the bark of the Western yew, Taxus brevifolia Nut (Taxaceae), and was found to have antitumor and antileukemic activity ²³. It has subsequently been found in the roots, leaves, and stems of this tree and related members of the yew family. It is a complex ester with an unusual structure consisting of an oxetan ring attached to a derivative of taxane. Because of its unusual mechanism of action, it has become an important tool for investigating microtubule function. Its action and spectrum of antitumor activity have earned it a unique place in experimental therapeutics, and it is presently undergoing extensive clinical trials in a variety of cancers. The major barrier to paclitaxel’s earlier clinical development was its low abundance in the yew trees, since chemical synthesis had not been possible; there simply was not enough paclitaxel to do the appropriate trials. This situation has changed because of the development of novel synthetic methods and the identification of new sources of the taxanes. For example, docetaxel is extracted from the leaves of the European yew tree, leaves being a renewable resource. Thus, much progress has been made in basic and clinical studies of the taxanes ^24-26.

Mechanism of Action:

Among antineoplastic drugs that interfere with microtubules, paclitaxel exhibits a unique mechanism of action and for this reason has been studied extensively ^26-28. Paclitaxel promotes assembly of microtubules by shifting the equilibrium between soluble tubulin and microtubules toward assembly, reducing the critical concentration of tubulin required for assembly. The result is stabilization of microtubules, even in the presence of conditions (e.g., low temperature, high calcium) that normally promote disassembly of microtubules ²⁹. The remarkable stability of microtubules induced by paclitaxel is damaging to cells because of the perturbation in the dynamics of various microtubule-dependent cytoplasmic structures that are required for such functions as mitosis, maintenance of cellular morphology, shape changes, neurite formation, locomotion, and secretion. Microtubules are the only known biochemical targets of paclitaxel, and the many biologic effects observed in paclitaxel-treated cells are thought to arise from perturbations of microtubule dynamics.

Epothilones:

Although not derived from plants, the epothilones are novel antimicrotubule agents that were originally isolated from the myxobacterium Sorangium cellulosum ³⁰. They have also been completely synthesized by novel methods, including antibody catalysis ^31-32. Although they have no obvious structural similarity to taxanes, a common pharmacophore has been proposed to be shared by epothilones, taxanes, and two other microtubule-stabilizing agents, eleutherobin and discodermolide. This putative common pharmacophore may explain why the epothilones and taxanes have similar biochemical and pharmacologic actions, and that is why they are included in this chapter on natural product antimicrotubule agents from plants. For example, the epothilones have been shown to stabilize microtubules. Indeed, these agents have been shown to compete for the paclitaxel binding site on microtubules. Cell lines expressing Pgp are cross-resistant to the epothilones, but to a substantially lesser extent than the taxanes. Despite their common actions, there are some differences: epothilones do not produce endotoxin-like activity in macrophages as doe’s paxlitaxel. Moreover, a derivative, desoxyepothilone B, has been shown to cure taxol-refractory human tumor xenografts ³³. Because of these preclinical activities and their general lack of cross-resistance in taxol-resistant cells, these agents are entering clinical trial and will be watched for their activity during the next few years.

Curcumin:

Turmeric, a spice obtained from the rhizome of Curcuma longa Linn. (zingiberaceae), has been regularly used for its coloring, flavoring and medicinal properties. Studies suggest that turmeric is a potent antimutagenic in-vivo against careionogens such as benzo (a) pyrene and methylcholanthrene and it is exertion effective in inhibiting the formation and excretion of urinary mutagens in smokers. The effects of turmeric and curcumin on chromosomal aberration frequencies induced by radiomimetic agent bleomycin were investigated in Chinese hamster ovary cells. When turmeric and curcumin were combined with bleomycin, neither turmeric nor curcumin prevented bleomycin - included chromosomal damage in any phases of cell cycle. Conversely, a potentiation of clastogenicity of bleomycin by curcumin was clearly observed during S an G2/S phases ³⁴.

Lutein and Zeaxanthin carotenoids might reduce risk of age related macular degeneration, which is caused by irreversible deterioration of macula lutea, yellow spot in retina of eye. Dark, leafy green vegetables, especially spinach and kale, are excellent sources of lutein and zeaxanthin ³⁵.

Berberine:

Berberine as potential antimutagen was extracted from the stem bark of Mahonia aquifolium belonging to family Berberidaceae. The antimutagenic potency of berberine was evaluated against acridine orange by using Euglena gracilis as an eukaryotic test model, based on ability of the test compound/fraction to prevent mutageninduced damage of chloroplast DNA. On last decade, bis-benzylisoquinoline and especially protoberberine alkaloids (e.g. berberine and jatorrhizine) have attracted considerable attention in this respect; protoberberines represent a structural class of organic cations & have been found to be a predominantly distributed in several genera of families Ranunculaceae and Berberidaceae (e.g. Berberis, Mahonia, Coptis). Berberine is the major representative of protoberberine alkaloids. The drug was screened for anticancer activity. Berberine exhibits ability to induce apoptosis in promyelocytic leukemia HL-60 and 3T3 fibroblast cells. In addition, some protoberberines are highly effective as cytotoxic agents against several carcinoma such as Hela, SVKO, Hep-2, primary culture from mouse embryo and human fibroblast cells; berberine showed highest cytotoxicity among alkaloids tested. Recently it has been reported that berberine possesses a dual topoisomerase I and II poisoning activity. From computed modeling studies protoberberine -DNA complexes suggest that these alkaloids are able to bind to host DNA by both intercalative and minor groove. All the above findings raise the possibility that protoberberines may be effective in deactivation of carcinogens and tumor promoters ³⁶.

Flavonoids:

A number of known prenylated flavonoids were isolated from Psoralea corylifolia using an assay procedure based on inhibition of the mutagenic action of 2-aminoanthrocene on Salmonella typhimurium. All of these compounds were toxic rather than an antimutagenic or desmutagenic. Bakuchial, a known prenylated phenolic terpene, was isolated. Biochanin A, a known isoflavone, was similarly isolated from Cicer arientinum and was active and nontoxic. Quercetin and myricetin flavonoids present in grapes are being investigated as potential anticarcinogens ³⁵.

Polyphenols:

Grape-seed extract, pine-bark extract and green tea are currently being studied for their polyphenols, compounds that appear to protect against various cancers in animal studies. Oligomeric proanthocyanidins (OPCs) are water-soluble, condensed tannins found in red wine, grape seeds and pine bark. In addition to their own antioxidant ability, OPCs have been found to spare other antioxidants such as vitamins C & E. Antioxidants such as OPCs might slow aging process & arrest cancer cells because they inhibit oxidants & free radicals that damage cells and tissue. They also strengthen blood vessels & reduce platelet aggregation, and may thus prevent circulatory problems ³².

Catechin:

On a dry-matter basis, polyphenols make up about 30% of fresh tea leaves. Catechins are primary phenolic compounds found in Green tea, Camellia sinensis which is also known, as Chinese tea, tea, green tea extract, green tea polyphenols, epigallocatechin gallate. The main constituents found in tea are caffeine, Flavonoids, theaflavin, Methylxanthines (Theophylline, Theobromine & theeanine, Polyphenols (Gallic acid) and catechins (gallocatechin, epigallocatechin, epicatechin and epigallocatechin gallate), Polysaccharides, Proanthocyanidins. Patients use tea as a dietary beverage and to prevent & treat cancer hyperlipidemia, hypertension, and atherosclerosis. The principal active constituent in green tea is epigallocatechin - 3 - gallate, which accounts for 40% of total polyphenol content of green tea extract. Caffeinated green tea may cause insomnia & nausea. Use of decaffeinated products may be preferred due to lower incidence to adverse event. Green tea polyphenols may reduce risk of prostate, breast, esophageal, lung, skin, pancreatic, & bladder cancers & oral leukoplakia. Theaflavin enriched green tea can be used to lower low density lipoprotein cholesterol. Some preliminary evidence shows that tea flavonoids such as quercetin, kaempferol, myricetin, apigenin & luteolin may reduce risk of heart diseases ³⁶.

Resveratrol:

A phenolic is found at high levels in purple grapes, grape juice, red wine and peanuts. It has also been associated with decreased risk of CHD. It is thought it lower risk of CHD by many mechanisms, including reduced aggregation of blood platelets, increased high density lipoprotein cholesterol, and various antioxidant mechanisms.Resveratrol was found to act as an antioxidant and antimutagen and to induce phase 11 drug –metabolising enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hyperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lessions in carcinogen- treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans ³⁷.

CONCLUSION:

Natural products play a dominant role in pharmaceutical care. This is especially obvious in the case of antitumor drugs, as exemplified by paclitaxel (Taxol@), vincristine (Oncovinm), vinorelbine (Na, velbine@), teniposide (Vumon@), and various water-soluble analogs of camptothecin (e.g., Hycamtin@). The most efficient method of discovering drugs such as these (i.e. novel chemical prototypes that may function through unique mechanisms of action) is bioactivity-guided fractionation, and it is certain that additional natural product drugs, some of which should be useful for the treatment of humans, remain to be discovered. For the commercial procurement of structurally complex natural product drugs, isolation from plant material may be most practical. Cancer chemopreventive agents, many of which are natural products, are capable of preventing or inhibiting the process of carcinogenesis.

REFERENCES:

1. Fu-Yue , J. Ren-Wang D. Research Progress of the Natural Products against Prostate Cancer. Chinese Journal of Natural Medicines 9(2), 81−89, 2011

2. JM. Pezzuto. Plant derived anticancer agents. Bio chemical pharmacology 33, 121-133, 1997

3. K. Larsen, AE. Escargueil, A. Skladanowski. Resistance mechanisms associated with altered intracellular distribution of anticancer agents. Pharmacology & Therapeutics 85 217–229, 2000

4. V. Zuco, R. Supino, SC. Righetti, L. Cleris, E. Marchesi, CG. Passerini, F. Formelli. Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Letters 175, 17–25, 2002

5. L. Pan, H. Chai, AD. Kinghorn. The continuing search for antitumor agents from higher plants. Phytochemistry Letters 3, 1–8, 2010

6. Duvoix, R. Blasius, S. Delhalle, M. Schnekenburger, F. Morceau, E. Henry, M. Dicato, M. Diederich, Chemopreventive and therapeutic effects of curcumin. Cancer Letters 223, 181–190, 2005

7. JH. Kessler, FB. Mullauer, GM. De Roo, JP. Medema. Broad in-vitro efficacy of plant-derived betulinic acid against cell lines derived from the most prevalent human cancer types.Cancer Letters 251, 132–145, 2007

8. P. Greenwald, CK. Clifford, JA. Milner. Diet and cancer prevention. European Journal of Cancer 37, 948–965, 2001

9. S. Nobili, D. Lippi, E. Witort, M. Donnini, L. Bausi, E. Minia, S. Capacciolic. Natural compounds for cancer treatment and prevention. Pharmacological Research 59, 365–378, 2009

10. RM. Conway, MC. Madigan, FA. Billson, PL. Penfold. Vincristine- and Cisplatin-induced Apoptosis in Human Retinoblastoma. Potentiation by Sodium Butyrate. European Journal of Cancer, 34(11), 1741-1748, 1998

11. M. Goodman, RM. Bostick, O. Kucuk, DP. Jones. Clinical trials of antioxidants as cancer prevention agents: Past, present, and future. Free Radical Biology & Medicine 51, 1068–1084, 2011

12. G. M. Cragg , DJ. Newman. Plants as a source of anti-cancer agents. Journal of Ethnopharmacology 100, 72–79, 2005

13. Y. Li, C. Li, Y. Sun, Y. Niu, L. Liu, Q. Mei. Are the ingredients extracted from fruits and vegetables superior to fruits and vegetables in cancer prevention? Medical Hypotheses 75, 77–78, 2010

14. S. J. Oha, O. Kim, JS. Lee, J. Kim, M. R. Kim, HS. Choi, JH. Shim, KW. Kang, YC. Kim. Inhibition of angiogenesis by quercetin in tamoxifen-resistant breast cancer cells. Food and Chemical Toxicology 48, 3227–3234, 2010

15. T. Sandhyaa, KM. Lathikaa, BN. Pandeyb, KP. Mishraa. Potential of traditional ayurvedic formulation, Triphala, as a novel anticancer drug. Cancer Letters 231, 206–214, 2006

16. Li Y, Ellis KL, Ali S, El-Rayes BF, Nedeljkovic-Kurepa A, Kucuk O, Philip PA, and Sarkar FH. Apoptosisinducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NFkappaB in BxPC-3 pancreatic cancer cell line. Pancreas28: e90–e95, 2004.

17. Lei W, Mayotte JE, and Levitt ML. Enhancement of chemosensitivity and programmed cell death by tyrosine kinase inhibitors correlates with EGFR expression in non-small cell lung cancer cells. Anticancer Res 19: 221–228, 1999.

18. Wietrzyk J, Boratynski J, Grynkiewicz G, Ryczynski A, Radzikowski C, and Opolski A. Antiangiogenic and antitumour effects in vivo of genistein applied alone or combined with cyclophosphamide. Anticancer Res 21: 3893– 3896, 2001.

19. Kumi-Diaka J and Townsend J. Toxic potential of dietary genistein isoflavone and beta-lapachone on capacitation and acrosome reaction of epididymal spermatozoa. J Med Food 6: 201–208, 2003.

20. Park JH, Oh EJ, Choi YH, Kang CD, Kang HS, Kim DK, Kang KI, and Yoo MA. Synergistic effects of dexamethasone and genistein on the expression of Cdk inhibitor p21WAF1/CIP1 in human hepatocellular and colorectal carcinoma cells. Int J Oncol 18: 997–1002, 2001.

21. Hillman GG, Forman JD, Kucuk O, Yudelev M, Maughan RL, Rubio J, Layer A, Tekyi-Mensah S, Abrams J, and Sarkar FH. Genistein potentiates the radiation effect on prostate carcinoma cells. Clin Cancer Res 7: 382–390,2001.

22. McDonnell CO, Holden G, Sheridan ME, Foley D, Moriarty M, Walsh TN, and Bouchier-Hayes DJ. Improvement in efficacy of chemoradiotherapy by addition of an antiangiogenic agent in a murine tumor model. J Surg Res 116: 19–23, 2004.

23. Akimoto T, Nonaka T, Ishikawa H, Sakurai H, Saitoh JI, Takahashi T, and Mitsuhashi N. Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell lines in vitro: possible involvement of inhibition of survival signal transduction pathways. Int JRadiat Oncol Biol Phys 50: 195–201, 2001

24. Papazisis KT, Zambouli D, Kimoundri OT, Papadakis ES, Vala V, Geromichalos GD, Voyatzi S, Markala D, Destouni E, Boutis L, and Kortsaris AH. Protein tyrosine kinase inhibitor, genistein, enhances apoptosis and cell cycle arrest in K562 cells treated with gamma-irradiation.Cancer Lett 160: 107–113, 2000.

25. Kubota T, Uemura Y, Kobayashi M, and Taguchi H. Combined effects of resveratrol and paclitaxel on lung cancer cells. Anticancer Res 23: 4039–4046, 2003.

26. Nicolini G, Rigolio R, Miloso M, Bertelli AA, and Tredici G. Anti-apoptotic effect of trans-resveratrol on paclitaxel-induced apoptosis in the human neuroblastoma SH-SY5Y cell line. Neurosci Lett 302: 41–44, 2001.

27. Manna SK, Mukhopadhyay A, and Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 164: 6509– 6519, 2000.

28. Jang JH and Surh YJ. Protective effect of resveratrol on beta-amyloid-induced oxidative PC12 cell death. Free Radic Biol Med 34: 1100–1110, 2003.

29. Zoberi I, Bradbury CM, Curry HA, Bisht KS, Goswami PC, Roti Roti JL, and Gius D. Radiosensitizing and antiproliferative effects of resveratrol in two human cervical tumor cell lines. Cancer Lett 175: 165–173, 2002.

30. Bharti AC, Donato N, Singh S, and Aggarwal BB. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 101: 1053–1062, 2003.

31. Hour TC, Chen J, Huang CY, Guan JY, Lu SH, and Pu YS. Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21(WAF1/CIP1) and C/EBPbeta expressions and suppressing NFkappaB activation. Prostate 51: 211–218, 2002.

32. Chendil D, Ranga RS, Meigooni D, Sathishkumar S, and Ahmed MM. Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. Oncogene 23: 1599–1607,2004.

33. Thresiamma KC, George J, and Kuttan R. Protective effect of curcumin, ellagic acid and bixin on radiation induced toxicity. Indian J Exp Biol 34: 845–847, 1996.

34. Thresiamma KC, George J, and Kuttan R. Protective effect of curcumin, ellagic acid and bixin on radiation induced genotoxicity. J Exp Clin Cancer Res 17: 431–434, 1998.

35. Inano H and Onoda M. Radioprotective action of curcumin extracted from Curcuma longa Linn: inhibitory effect on formation of urinary 8-hydroxy-2_-deoxyguanosine, tumorigenesis, but not mortality, induced by gamma-ray irradiation. Int J Radiat Oncol Biol Phys 53: 735–743, 2002.

36. Wall NR, O’Connor DS, Plescia J, Pommier Y, and Altieri DC. Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. Cancer Res 63: 230–235, 2003.

37. Ahmad KA, Clement MV, Hanif IM, and Pervaiz S. Resveratrol inhibits drug-induced apoptosis in human leukemia cells by creating an intracellular milieu nonpermissive for death execution. Cancer Res 64: 1452–1459, 2004.

Received on 30.12.2013 Modified on 18.01.2014

Asian J. Research Chem. 7(8): August 2014; Page 765-770