Peroxisome proliferator-activated receptor agonists and bladder cancer: lessons from animal studies

This article reviews available animal studies on the possible link between the use of peroxisome proliferator-activated receptor (PPAR) agonists and bladder cancer, with further discussion on the possible implications to humans. Carcinogenicity studies suggest that the PPARγ agonist pioglitazone and dual PPARα/γ agonists such as ragaglitazar, muraglitazar, and naveglitazar may increase the risk of bladder cancer in a dose-responsive pattern in rats. It is interesting that bladder cancer related to PPAR agonists shows remarkable species- and sex-specificity and has a predilection to occur in the ventral dome of bladder in rodents. While male rats treated with pioglitazone or muraglitazar have a higher propensity to develop bladder cancer than female rats, mice of both sexes do not develop bladder cancer even when exposed to very high doses. Direct genotoxicity or cytotoxicity of PPAR agonists is unlikely to be the mode of action because most of the parent compounds or their metabolites of the PPAR agonists are neither mutagenic nor genotoxic, and they are rarely excreted in the urine; but a receptor-mediated PPAR effect cannot be excluded. Some suggest a "urolithiasis hypothesis" referring to the formation of urinary solids and calculi, which subsequently causes bladder necrosis, regenerative proliferation, hypertrophy, and cancer. However, whether these animal findings could have human relevance is not yet fully understood. Some argue that the urolithiasis-induced bladder cancer might be rat-specific and would probably not be applicable to humans. An effect of increased urinary growth factors induced by PPAR agonists has also been proposed, but this requires more investigations. Before fully clarified, a balance between the risks and benefits of the use of pioglitazone, an approved oral antidiabetic agent that has recently been linked to an increased but not yet confirmed risk of bladder cancer in humans, should be justified for individual use.