Abstract
Cancer chemoprevention has traditionally been defined as a dietary or therapeutic approach for the prevention, delay, or reversal of carcinogenesis. We currently expand this definition to include nontoxic applications for patients with established disease. In this context, efficacy can be achieved by selectively altering cell-cycle progression. In the quest for new cancer chemopreventive agents, we have focused on the isolation of natural products as lead molecules, followed by synthetic modification to improve activity. Using biologic response as a guide for fractionation, over 200 active compounds have been identified. Some of the most interesting include brassinin and 4′-bromoflavone as inducers of quinone reductase, deguelin as an inhibitor of ornithine decarboxylase, resveratrol as an inhibitor of cyclooxygenase, and brusatol as an inducer of cellular differentiation. These agents have demonstrated effectiveness in experimental models of carcinogenesis. Further development of these agents as chemopreventive drugs may proceed through the normal regulatory process (eg, 4′-bromoflavone). Alternatively, some natural products may be administered as dietary supplements (eg, resveratrol). In either case, chemoprevention offers great hope in reducing the morbidity and mortality associated with cancer.
Similar content being viewed by others
References
Goldsmith DF: Linking environmental cancer with occupational epidemiology research: the role of the International Agency for Research on Cancer (IARC). J Environ Pathol Toxicol Oncol 2000, 19:171–175.
Sporn MB, Dunlop NM, Newton DL, Smith JM: Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 1976, 35:1332–1338. This seminal paper helped to define the concept of cancer chemoprevention.
Sporn MB, Hong KW: Recent advances in chemoprevention of cancer. Science 1997, 278:1073–1077. A good contemporary review of the field of cancer chemoprevention.
Kelloff GJ, Sigman CC, Greenwald P: Cancer chemoprevention: progress and promise. Eur J Cancer 1999, 35:2031–2038.
Moon RC, Mehta RG, Rao KVN: Retinoids in experimental animals. In The Retinoids: Biology, Chemistry and Medicine. Edited by Sporn MB, Roberts AB, Goodman DS. New York: Raven Press; 1997:573–595.
Wattenberg LW: Chemoprevention of cancer. Cancer Res 1985, 45:1–8.
Weisburger JH: Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants, and carotenoids. Am J Clin Nutr 1991, 53:226S-237S.
Park EJ, Pezzuto JM: Autoxidation and antioxidants. In Encyclopedia of Pharmaceutical Technology, edn 2. Edited by Swarbrick J, Boylan JC. New York: Marcel Dekker; 2001:97–113.
Decensi A, Costa A: Recent advances in cancer chemoprevention, with emphasis on breast and colorectal cancer. Eur J Cancer 2000, 36:694–709.
Elstner E, Linker-Israeli M, Said J, et al.: 20-epi-Vitamin D3 analogues: a novel class of potent inhibitors of proliferation and inducers of differentiation of human breast cancer cell lines. Cancer Res 1995, 55:2822–2830.
Garland CF, Garland FC, Gorham ED: Calcium and vitamin D: their potential roles in colon and breast cancer prevention. Ann N Y Acad Sci 1999, 889:107–119.
Crowell PL: Prevention and therapy of cancer by dietary monoterpenes. J Nutr 1999, 129:775S-778S.
Lupulescu A: Prostaglandins, their inhibitors and cancer. Prostaglandins Leukot Essent Fatty Acids 1996, 54:83–94.
Cuendet M, Pezzuto JM: The role of cyclooxygenase and lipoxygenase in cancer chemoprevention. Drug Metab Drug Interac 2000, 17:109–157.
Verma AK: Inhibition of tumor promotion by DL-alphadifluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase. Basic Life Sci 1990, 52:195–204.
Yang K, Lamprecht SA, Liu Y, et al.: Chemoprevention studies of the flavonoids quercetin and rutin in normal and azoxymethane-treated mouse colon. Carcinogenesis 2000, 21:1655–1660.
Ip MM, Masso-Welch PA, Shoemaker SF, et al.: Conjugated linoleic acid inhibits proliferation and induces apoptosis of normal rat mammary epithelial cells in primary culture. Exp Cell Res 1999, 250:22–34.
Lu LJ, Anderson KE, Grady JJ, et al.: Decreased ovarian hormones during a soya diet: implications for breast cancer prevention. Cancer Res 2000, 60:4112–121.
Ip C, Thompson HJ, Zhu Z, Ganther HE: In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention. Cancer Res 2000, 60:2882–2886.
Kennedy AR: The Bowman-Birk inhibitor from soybeans as an anticarcinogenic agent. Am J Clin Nutr 1998, 68:1406S-1412S.
Agarwal R: Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents. Biochem Pharmacol 2000, 60:1051–1059.
Burger AM, Zhang X, Seth A: Detection of novel genes that are up-regulated (Di12) or down-regulated (T1A12) with disease progression in breast cancer. Eur J Cancer Prev 1998, 1:529–535.
Berwick M, Vineis P: Markers of DNA repair and susceptibility to cancer in humans: an epidemiologic review. J Natl Cancer Inst 2000, 92:874–897.
Clapper ML, Szarka CE: Glutathione S-transferases biomarkers of cancer risk and chemopreventive response. Chem Biol Interact 1998, 24:377–388.
Weinstein IB: Relevance of cyclin D1 and other molecular markers to cancer chemoprevention. J Cell Biochem Suppl 1996, 25:2–28.
Primiano T, Yu R, Kong A-NT: Signal transduction events elicited by natural products that function as cancer chemopreventive agents. Pharm Biol 2002, in press.
Seo HJ, Surh YJ: Eupatilin, a pharmacologically active flavone derived from Artemisia plants, induces apoptosis in human promyelocytic leukemia cells. Mutation Res 2001, 496:191–198.
Yun TK: Update from Asia: Asian studies on cancer chemoprevention. Ann N Y Acad Sci 1999, 889:157–192.
Kinghorn AD, Fong HHS, Farnsworth NR, et al.: Cancer chemopreventive agents discovered by activity guided fractionation: a review. Curr Org Chem 1998, 2:597–612.
Pezzuto JM, Song LL, Lee SK, et al.: Bioassay methods useful for activity-guided isolation of natural product cancer chemopreventive agents. In Chemistry, Biological and Pharmacological Properties of Medicinal Plants from the Americas, 1998. Edited by Hostettmann K, Gupta MP, Marston A. Chur, Switzerland: Harwood Academic Publishers; 1998:81–110. A summary of the design and conduct of natural product drug discovery.
Loub WD, Farnsworth NR, Soejarto DD, Quinn ML: NAPRALERT: computer handling of natural product research data. J Chem Inf Comput Sci 1985, 25:99–103.
Iwamoto M, Ohtsu H, Tokuda H, et al.: Anti-tumor promoting diterpenes from the stem bark of Thuja standishii (Cupressaceae). Bioorg Med Chem 2001, 9:1911–1921.
Saleem M, Alam A, Sultana S: Asafoetida inhibits early events of carcinogenesis: a chemopreventive study. Life Sci 2001, 68:1913–1921.
Mehta RG, Moriarty RM, Mehta RR, et al.: Prevention of preneoplastic mammary lesions by a novel vitamin D analog, 1alpha-hydroxyvitamin D5. J Natl Cancer Inst 1997, 89:212–218.
Mehta RG, Bhat KPL, Hawthorne MH, et al.: Induction of atypical ductal hyperplasia in mouse mammary gland organ culture. J Natl Cancer Inst 2001, 93:1103–1106. This paper introduces the use of mouse mammary organ culture as a model for ductal hyperplasia.
Mehta RG, Liu J, Constantinou A, et al.: Cancer chemopreventive activity of brassinin, a phytoalexin from cabbage. Carcinogenesis 1995, 16:399–404.
Gerhäuser C, Mar W, Lee SK, et al.: Rotenoids mediate potent chemopreventive activity through transcriptional regulation of ornithine decarboxylase. Nat Med 1995, 1:260–266.
Song LL, Kosmeder JW, Lee SK, et al.: Cancer chemopreventive activity mediated by 4′-bromoflavone, a potent inducer of Phase II detoxification enzymes. Cancer Res 1999, 59:578–585.
Mata-Greenwood E, Ito A, Westenburg H, et al.: Discovery of novel inducers of cellular differentiation iusing HL-60 promyelocytic cells. Anticancer Res 2001, 21:1763–1770.
Jang M, Cai L, Udeani G, et al.: Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997, 275:218–220. This paper established the cancer chemopreventive potential of resveratrol.
Mehta RG: Experimental basis for breast cancer. Eur J Cancer 2000, 36:1275–1282.
Gerhäuser C, Lee SK, Kosmeder JW, et al.: Regulation of ornithine decarboxylase induction by deguelin, a natural product cancer chemopreventive agent. Cancer Res 1997, 57:3429–3435.
Udeani GO, Gerhäuser C, Thomas CF, et al.: Cancer chemopreventive activity mediated by deguelin, a naturally occuring rotenoid. Cancer Res 1997, 57:3424–3428.
Bhat KPL, Kosmeder JW II, Pezzuto JM: Biological effects of resveratrol [review]. Antiox Redox Signal 2001, 3:1047–1064.
Hsieh TC, Wu JM: Grape-derived chemopreventive agent resveratrol decreases prostate-specific antigen (PSA) expression in LNCaP cells by an androgen receptor (AR)-independent mechanism. Anticancer Res 2000, 20:225–228.
Bhat KP, Lantvit D, Christov K, et al.: Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res 2001, 61:7456–7463.
Zhang Y, Kensler TW, Cho CG, et al.: Anticarcinogenic activity of sulforaphane and structurally related isothiocyanates. Proc Natl Acad Sci U S A 1994, 91:3147–3150.
Gerhäuser C, You M, Liu J, et al.: Cancer chemopreventive potential of sulforamate, a novel analog of sulforaphane that induces phase II metabolizing enzymes. Cancer Res 1997, 57:272–278.
Alberts DS, Colvin OM, Conney AH, et al.: Prevention of cancer in the next millennium: report of the Chemoprevention Working Group to the American Association for Cancer Research. Cancer Res 1999, 59:4743–4758. A comprehensive evaluation of the importance of cancer chemoprevention, with a future perspective provided.
Planck M: The Philosophy of Physics. New York: WW Norton & Company; 1936.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mehta, R.G., Pezzuto, J.M. Discovery of cancer preventive agents from natural products: From plants to prevention. Curr Oncol Rep 4, 478–486 (2002). https://doi.org/10.1007/s11912-002-0059-2
Issue Date:
DOI: https://doi.org/10.1007/s11912-002-0059-2