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Invited Abstract: Mechanisms of Chemoprevention with Foods

Novel approaches for chemoprevention of colon cancer by food components.

Susan Lehman Cullman Cancer Research Lab., Piscataway, NJ

Abstract

PL05-03

Epidemiological studies have provided evidence that dietary factors particularly caloric intake, and saturated fat may increase the risk of colon cancer whereas dietary fish oil and olive oil reduce the risk. Several preclinical studies using well-established laboratory animal models provided experimental evidence that diets containing high levels of saturated fats such as those in Western diets promote colon carcinogenesis, whereas diets high in fish oil or olive oil had no such promoting effect. Epidemiological studies have provided initial leads for the identification of naturally occurring candidate chemopreventive agents from fruits, vegetables and grains which are principal sources of micronutrients and several minor constituents including isoflavanoids, triterpinoids, polyphenols, isothiocyanates, and ligans, to cite a few. The observation that these dietary components exhibit biochemical and physiological properties analogous to those of pharmaceutical agents has fostered increased interest in reasons for the use of such dietary components as potential chemopreventive agents in reducing the risk of cancer. It is noteworthy that curcumin derived from the rhisome of tumeric plant has been shown to possess antiinflammatory activity and is less toxic than the nonsteroidal antiinflammatory drugs (NSAIDs). Even at 8 grams/day, curcumin didn't induce any adverse side effects. Among the naturally occurring antiinflammatory agents, curcumin was extensively studied and proved to be an inhibitor of several types of chemically-induced neoplasia. Curcumin has been shown to inhibit colon tumorigenesis when given during the initiation and promotion/progression stages of colon carcinogenesis. With regard to mode of action, curcumin inhibits cyclooxygenase-2, inducible nitric oxide synthase and Lipoxygease (LOX) activities and NFkB activation and induced apoptosis. Phenylethyl caffeate and its analogue, phenylyethyl methylcaffeate which are major components of propolis in the honey beehive that possess antiinflammatory acivities have been shown to inhibit colon carcinogenesis in laboratory animal models. Triterpenoids such as oleanolic acid and its analogues have been shown to suppress COX-2 activity, and LOX activity and colon carcinogenesis. This information suggests that several phytochemicals that posses antiinflammatory activity may be effective chemopreventive agents. Our results and those of others suggest this nutritional prevention has the potential to be a major component of colorectal cancer control, especially primary prevention in general population. It should be recognized that intervention with diet modification alone may not be sufficient for secondary prevention of colorectal cancer in high risk patients such as those with hereditary polyposia and sporadic colon polyps. However, intervention by diet modification along with chemopreventive agents is an ideal strategy for secondary prevention of colon cancer in these high-risk patients to prevent the progression or events leading to malignant neoplasia. An important strategy to reduce the risks associated with the use of pharmacological agents is to identify combinations of agents with different modes of action that are very effective at very low doses. This approach is very important when a promising chemopreventive agent demonstrates significant efficacy but may produce toxic effects at high doses. These data support the concept that combination of chemopreventive agents can have beneficial applications in human colon cancer chemoprevention trials. The use of low doses of pharmacological agents with different modes of action in combination with healthy lifestyles seems to be a promising approach that may evolve into a better chemopreventive strategy for future human clinical trials. (Supported by USPHS grant CA-37763 from the National Cancer Institute).