Isolation and evaluation of natural product cancer chemopreventive agents Free

CN05-02

Throughout history, natural products have played a dominant role in the treatment of human ailments. The association of salicylates with the willow, and quinine with cinchona, are renowned examples. Similarly, the legendary discovery of penicillin transformed global existence. Traditional remedies, largely based on terrestrial plants, still dominate therapeutic practices throughout the world, and natural products comprise a large portion of current-day pharmaceutical agents, most notably in the areas of antibiotic and cancer therapies (1). Similarly, natural products are of major importance in the field of cancer chemoprevention (2). Prominent examples include sulforaphane and phenethyl isothiocyanate (cruciferous vegetables), epigallocatechin-3-gallate (green tea), curcumin (turmeric), resveratrol (grapes), sulfur-containing compounds and selenium (the genus Allium), and lycopene (tomatoes) (3). Clinical trials demonstrate promise (4). Consequently, it is reasonable to search for new natural product cancer chemopreventive agents.
 For the discovery of novel natural chemopreventive agents, one approach is to evaluate crude natural products, such as plant extracts, and isolate active principles. Following biological activity, standard methods of fractionation can be employed. If a suitable receptor or target enzyme is available, the more efficient process of ultrafiltration-mass spectrometry can be used (5). Mass spectrometry is also a useful tool for studying the absorption and metabolism of lead compounds (6,7). Resulting information is crucial when considering future development.
 Largely using terrestrial plants as starting materials, we have isolated and identified a large number of promising cancer chemopreventive agents (8). A notable example is resveratrol (9), a constituent of grapes and grape products, that now has been the subject of nearly 2,000 manuscripts and clinical trials (10). Resveratrol is readily absorbed, but only small quantities of the parent compound are found in the serum of humans. This illustrates the importance of metabolism and the corresponding activity of metabolites. Through crystallographic analysis, we have observed resveratrol interaction at the arachidonic acid binding site of cyclooxygenase, but perhaps more importantly, the 4’-sulfate metabolite is capable of a similar interaction. It logically follows that synthetic organic chemistry is an integral component of cancer chemopreventive drug development, from the perspective of creating derivatives and metabolites (11), as well as scale-up synthesis to provide adequate quantities of lead compounds for testing (12).
 Although edible and nonedible terrestrial plants have yielded interesting leads, a new and exciting area of research involves exploring the biodiversity provided by microbes of the marine environment (13). Already, promising leads have been discovered for cancer therapy (13). Recently, as chemopreventive agents, two unusual bicyclic polyketides obtained from the marine actinomycete Salinispora arenicola were found to inhibit ornithine decarboxylase induction in cell culture (14), similar to the mode of action of rotenoids (15). Clearly, cancer chemopreventive potential still requires further exploration. We have now established a novel battery of assays, such as interaction with RxR or Keap1, and inhibition of quinone reductase 2 or NF-kappaB, and many active leads have been identified. As a result, we are confident that a variety of novel substances of marine origin will be discovered as a result of this work.
 It is now well established that cancer chemoprevention is a viable strategy in the fight against cancer. The current armamentarium of agents has resulted largely from epidemiological observations, off-shoots of cancer therapeutic agents, or agents that were used for other therapeutic indications. With concerted effort involving a range of expertise, it is clear that new natural product chemopreventive agents with clinical potential can be uncovered using a systematic approach of drug discovery.
 Acknowledgement
 The authors are grateful to the National Cancer Institute for support provided under the auspices of program project P01 CA48112 entitled “Natural Inhibitors of Carcinogenesis.”
 Literature Cited
 1. Newman, D.J., Cragg, G.M., and Snader, K.M. Natural products as sources of new drugs over the period of 1981-2002. J. Nat. Prod. 66: 1022-1037, 2003.
 2. Pezzuto, J.M. Plant-derived anticancer agents. Biochem. Pharmacol. 53: 121-133, 1997.
 3. Park, E.J. and Pezzuto, J.M. Botanicals in cancer chemoprevention. Cancer Metast. Rev. 21: 231-255, 2002.
 4. Kelloff, G.J., Sigman, C.C., and Greenwald, P. Cancer chemoprevention: progress and promise. Eur. J. Cancer 35: 1755-1762, 1999.
 5. Liu, G., Eggler, A.L., Dietz, B.M., Mesecar, A.D., Bolton, J.L., Pezzuto, J.M., and van Breemen, R.B. Screening method for the discovery of potential cancer chemoprevention agents based on mass spectrometric detection of alkylated Keap1. Anal. Chem. 77: 6407-6414, 2005.
 6. Li, Y., Grubjesic, S., Nikolic, D., Zhu, D., Kosmeder, J.W., Moriarty, R.M., Pezzuto, J.M., and van Breemen, R.B. In vitro assessment of intestinal permeability and hepatic metabolism of 4'-bromoflavone, a promising cancer chemopreventive agent. Xenobiotica 34: 535-547, 2004.
 7. Li, Y., Shin, Y.G., Yu, C., Kosmeder, J.W., Hirschelman, W.H., Pezzuto, J.M., and van Breemen, R.B. Increasing the throughput and productivity of Caco-2 cell permeability assays using liquid chromatography-mass spectrometry: application to resveratrol absorption and metabolism. Comb. Chem. High Throughput Screen. 6: 757-767, 2003.
 8. Pezzuto, J.M., Kosmeder II, J.W., Park, E.J., Lee, S.K., Cuendet, M., Gills, J., Bhat, K., Grubjesic, S., Park, H.-S., Mata-Greenwood, E., Tan, Y.M., Yu, R., Lantvit, D.D., and Kinghorn, A.D. Characterization of Natural Product Chemopreventive Agents. In: G.J. Kelloff, E.T. Hawk, and C.C. Sigman (eds.), Cancer Chemoprevention, Volume 2: Strategies for Cancer Chemoprevention. Totowa, New Jersey: Humana Press Inc., pp. 3-37, 2005.
 9. Jang, M., Cai, L., Udeani, G.O., Slowing, K., Thomas, C.F., Beecher, C.W.W., Fong, H.H.S., Farnsworth, N.R., Kinghorn, A.D., Mehta, R.G., Moon, R.C., and Pezzuto, J.M. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275: 218-220, 1997
 10. Pezzuto, J.M. Resveratrol as a cancer chemopreventive agent. In: B.B. Aggarwal and S. Shishodia (eds.), Resveratrol in Health and Disease, New York, New York: Marcel Dekker, Inc, pp. 233-383, 2006.
 11. Maiti, A., Cuendet, M., Croy, V.L., Endringer, D.C., Pezzuto, J.M., and Cushman, M. Synthesis and biological evaluation of (±)-abyssinone II and its analogues as aromatase inhibitors for chemoprevention of breast cancer. J. Med. Chem. 50: 2799-2806, 2007.
 12. Maiti, A., Cuendet, M., Kondratyuk, T., Croy, V.L., Pezzuto, J.M., and Cushman, M. Synthesis and cancer chemopreventive activity of zapotin, a natural product from Casimiroa edulis. J. Med. Chem. 50: 350-355, 2007.
 13. Fenical, W. and Jensen, P.R. Developing a new resource for drug discovery: Marine actinomycete bacteria. Nature Chem. Biol. 2: 666-673, 2006.
 14. Williams, P.G., Asolkar, R.N., Kondratyuk, T., Pezzuto, J.M., Jensen, P.R., and Fenical, W. Saliniketals A and B, bicyclic polyketides from the marine actinomycete Salinispora arenicola. J. Nat. Prod. 70: 83-88, 2007.
 15. Gerhäuser, C., Mar, W., Lee, S.K., Suh, N., Luo, Y., Kosmeder, J., Moriarty, R.M., Luyengi, L., Kinghorn, A.D., Fong, H.H.S., Mehta, R.G., Constantinou, A., Moon, R.C., and Pezzuto, J.M. Rotenoids mediate potent chemopreventive activity through transcriptional regulation of ornithine decarboxylase. Nature Medicine 1: 260-266, 1995.