Minireview Peroxisome Proliferator-activated Receptor Modulators As Potential Chemopreventive Agents

Peroxisome proliferator-activated receptors (PPARs), members of the superfamily of nuclear steroid hormone receptors, have traditionally been studied for their role in lipid, glucose, and energy homeostasis. Recent evidence suggests that pharmacological activation of PPAR and PPAR , and inhibition of PPAR , may prevent cancer. PPAR agonists induce differentiation, inhibit the growth of established tumor cells in vitro and in vivo, and have chemopreventive effects in animal models. PPAR has anti-inflammatory and differentiating activity and protects against the oxidative damage associated with aging. In contrast, PPAR expression may be a factor in colorectal carcinogenesis. PPAR is normally repressed by the adenomatous polyposis coli tumor suppressor gene, and impaired adenomatous polyposis coli is strongly associated with human colorectal cancer risk. This review presents a rationale for using PPAR modulators as cancer chemopreventive drugs. Introduction PPARs are ligand-activated transcription factors that heterodimerize with the RXRs and bind to peroxisomal proliferator response elements in the promoter region of target genes. Three PPAR isoforms have been cloned ( , , and ), each exhibiting distinct patterns of tissue distribution and ligand specificity. PPAR regulates numerous aspects of fatty acid catabolism, whereas PPAR controls adipocyte differentiation, systemic glucose levels, and lipid homeostasis (reviewed in Refs. 1 and 2). PPAR is involved in development, embryo implantation, myelination of the corpus callosum, lipid metabolism, and epidermal cell proliferation (3, 4). Significant species differences in response to PPAR , but not PPAR , have been noted. Specifically relevant to cancer, PPAR agonists increase peroxisomes and induce hepatomegaly and liver cancer in rodents. However, humans are refractory to the hepatotoxic actions of these drugs (reviewed in Ref. 5). In the following sections, evidence is presented for each PPAR class and the specific PPAR agonists that may play a role in cancer chemoprevention.