Can PPAR gamma ligands be used in cancer therapy?

Abstract

The role of peroxisome-proliferator activated receptor (PPAR)gamma in tumor growth inhibition has been extensively studied during last seven years but still remains debated. Many in vitro and xenograft studies have demonstrated that PPARgamma ligands are anti-tumorigenic due to anti-proliferative, pro-differentiation and anti-angiogenic effects. In animal models, PPARgamma ligands have shown preventive effects against chemical carcinogenesis. On the other hand, evidences are accumulating against the possible use of this ligand activated nuclear receptor in molecular targeting for cancer therapy. The growth inhibitory effects of certain PPARgamma ligands have recently been shown to be independent of PPARgamma-activation. Studies have also come up with results indicating the growth promoting effects of PPARgamma-activation, particularly in certain animal models genetically predisposed to cancer development. Loss-of-function mutations of PPARgamma in tumors and increased susceptibility of PPARgamma heterozygote knockout mice to carcinogenesis suggested a tumor-suppressing role of PPARgamma. However, recent findings do not support PPARgamma as a tumor suppressor gene. Although initial clinical trials with PPARgamma ligand troglitazone reported promising results in liposarcoma and prostate cancers, recent studies failed to show the expected therapeutic values in advanced colorectal and breast cancers. In this review, we have addressed these controversies on potential use of PPARgamma ligands in cancer therapy.