Role Of Peroxisome Proliferator Activated Receptor-Gamma In Bacillus Calmette-Guerin Bladder Cancer Therapy

Purpose: We evaluated the effects of combined PPARg agonist with bacillus Calmette-Guerin in bladder cancer growth in vitro and in vivo, focusing on the tissue remodeling mechanisms induced by bacillus Calmette-Guerin.Materials and Methods: PPARs are a superfamily of nuclear receptors that are transcription factors activated by ligands. Activation of PPARg, the gamma subtype, causes proliferation inhibition or differentiation of tumor cells. Previously, we reported that the inhibition of murine bladder tumor growth induced by bacillus Calmette-Guerin, which is the standard treatment for patients with nonmuscle invasive, high grade bladder cancer, increased PPARg expression in vitro and in vivo. In vitro the cell growth inhibition induced by bacillus Calmette-Guerin was enhanced by the PPARg agonist 15-d-PGJ2, raising the possibility that PPARg activation may be a therapeutic modality for this disease.Results: In MB49 cells bacillus Calmette-Guerin and 15-d-PGJ2 induced PPARg expression, nuclear translocation and transcriptional activity. In vivo bacillus Calmette-Guerin reduced tumor size, an effect that was partially reversed when bacillus Calmette-Guerin was combined with the PPARg agonist rosiglitazone. The same result was found when we analyzed the effect of the PPARg antagonist BADGE (Fluka Chemical, Buchs, Switzerland) combined with bacillus Calmette-Guerin. Analysis of the activation of macrophages and fibroblasts demonstrated that rosiglitazone inhibited the tissue remodeling mechanisms induced by bacillus Calmette-Guerin.Conclusions: Results suggest that PPARg is involved in the antitumor action of bacillus Calmette-Guerin. However, exogenous PPARg agonists would not be a favorable therapeutic modality because they can inhibit the tissue remodeling needed for an overall satisfactory bacillus Calmette-Guerin response.