Chemopreventive Effect of Peroxisome Proliferator

Peroxisome proliferator–activated receptor ; (PPAR;) is known to be expressed in several cancers, and the treatment of these cancer cells with PPAR; ligands often induces cell differentiation and apoptosis. Recently, the chemopreventive potential of PPAR; ligands on colon carcinogenesis was reported, although the effect of PPAR; on colon carcinogenesis and the mechanism of the effect remain controversial. In this study, we attempted to elucidate the role of PPAR; in gastric carcinogenesis and explored the possible use of PPAR; ligand as a chemopreventive agent for gastric cancer. N-methyl-N-nitrosourea (MNU, 240 ppm) was given in drinking water for 10 weeks to induce gastric cancer in PPAR; wild-type (+/+) and heterozygous-deficient (+/ ) mice, followed by treatment with PPAR; ligand [troglitazone, 0.15% (w/w) in powder food] or the vehicle alone for 42 weeks. At the end of the experiment, PPAR; (+/ ) mice were more susceptible to MNU-induced gastric cancer than wild-type (+/+) mice (89.5%/55.5%), and troglitazone significantly reduced the incidence of gastric cancer in PPAR; (+/+) mice (treatment 55.5%/vehicle 9%) but not in PPAR; (+/ ) mice. The present study showed that (a) PPAR; suppresses gastric carcinogenesis, (b) the PPAR; ligand troglitazone is a potential chemopreventive agent for gastric carcinogenesis, and (c) troglitazone’s chemopreventative effect is dependent on PPAR;. (Cancer Res 2005; 65(11): 4769-74)