Peroxisome proliferator-activated receptor-γ antagonists exhibit potent antiproliferative effects versus many hematopoietic and epithelial cancer cell lines

Peroxisome proliferator-activated receptor-γ ligands have preclinical and clinical anticancer activity. Most studies in this area address agonists, with relatively few reports on anticancer effects of peroxisome proliferator-activated receptor-γ antagonists. Thus, we evaluated the two pure peroxisome proliferator-activated receptor-γ antagonists, T0070907 and GW9662, on a panel of hematopoietic and epithelial cell lines. The peroxisome proliferator-activated receptor-γ antagonists and a reference agonist (pioglitazone) were tested in an in-vitro proliferation assay on a panel of seven hematopoietic and nine epithelial cancer cell lines, some of which are chemoresistant. Peroxisome proliferator-activated receptor-γ expression was measured by immunoblotting, as was the effect of treatment with these agents on peroxisome proliferator-activated receptor-γ levels. The effect of exogenous interleukin-6, an antiapoptotic cytokine, on growth inhibition was evaluated as well as the apoptotic effects of these drugs. The peroxisome proliferator-activated receptor-γ antagonists showed significantly greater potency on all cell lines (IC50s of 3.2–29.7 versus 26.5–78.7 μmol/l for pioglitazone) and greater maximum growth inhibition. Peroxisome proliferator-activated receptor-γ levels did not correlate with growth inhibition in this panel of cell lines. Combinations of peroxisome proliferator-activated receptor-γ antagonists and the agonist actually showed schedule-dependent increases in growth inhibition. Exogenous interleukin-6 did not induce resistance to these agents. Both the antagonists and the agonist induced apoptosis, but only the former drugs showed caspase dependence. These two peroxisome proliferator-activated receptor-γ antagonists have significantly more potent in-vitro antiproliferative effects versus hematopoietic and epithelial cancer cell lines. This effect does not correlate with peroxisome proliferator-activated receptor-γ levels, suggesting alternative mechanisms or other targets of action. These findings support further translational studies to explore the mechanism of action and therapeutic potential of this class of agents.