Potential of peroxisome proliferator-activated receptor gamma antagonist compounds as therapeutic agents for a wide range of cancer types

Abstract

PPARgamma is a therapeutic target that has been exploited for treatment of type II diabetes mellitus (T2DM) with agonist drugs. Since PPARgamma is expressed by many hematopoietic, mesodermal and epithelial cancers, agonist drugs were tested and shown to have both preclinical and clinical anticancer activities. While preclinical activity has been observed in many cancer types, clinical activity has been observed only in pilot and phase II trials in liposarcoma and prostate cancer. Most studies address agonist compounds, with substantially fewer reports on anticancer effects of PPARgamma antagonists. In cancer model systems, some effects of PPARgamma agonists were not inhibited by PPARgamma antagonists, suggesting noncanonical or PPARgamma-independent mechanisms. In addition, PPARgamma antagonists, such as T0070907 and GW9662, have exhibited antiproliferative effects on a broad range of hematopoietic and epithelial cell lines, usually with greater potency than agonists. Also, additive antiproliferative effects of combinations of agonist plus antagonist drugs were observed. Finally, there are preclinical in vivo data showing that antagonist compounds can be administered safely, with favorable metabolic effects as well as antitumor effects. Since PPARgamma antagonists represent a new drug class that holds promise as a broadly applicable therapeutic approach for cancer treatment, it is the subject of this review.

Figure 1

The chemical structures of four PPARγ antagonists: (1) GW9662, (2) T0070907, (3) SR-202, and (4) BADGE.

Figure 2

Dose-response curves for the MM line, KMS12-PE, to T0070907, both in the presence and absence of the hLL1 mAb. Square symbols represent the dose-response curve in the presence of hLL1, and diamond symbols represent the curve in the absence of LL1. The ordinate shows percent growth inhibition values and the abscissa the concentration of T0070907 in micromolar.