Effects of Thiazolidinediones on metabolism and cancer: Relative influence of PPARγ and IGF-1 signaling

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor-gamma (PPARγ) agonists. TZDs are orally effective medicines for metabolic syndrome and type 2 diabetes. In addition to metabolic effects these molecules also possess anti-cancer effects. Data from diabetes clinical trials also support anti-cancer effects of TZDs. The anti-cancer effects of TZDs neither correlate well with their ability to activate PPARγ receptor, nor are affected by the presence of PPARγ receptor antagonists. Accumulating evidence suggests that TZDs act as selective inhibitors of insulin-like growth factor-1 (IGF-1) receptor signaling, and IGF-1 signaling is known to be aberrantly regulated in various cancers. Structural analysis of TZDs suggest that the presence of 5-exo C–C single bond of the thiazolidine-2,4-dione ring is important for the metabolic effects but not for anti-cancer effects, as inclusion of C=C double bond at this position promotes antagonistic properties to the PPARγ receptor without compromising its anti-proliferative effects. The objectives of this review includes summarization of the relative influence of TZDs on PPARγ and IGF-1 signaling in mediating pharmacological effects, and to discuss the possibility of multiple pharmacophores, and thereby independent regulation of PPARγ and IGF-1 signaling.