Synergistic Effects of PPARgamma Ligands and Retinoids in Cancer Treatment.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. The activation of PPARs by their specific ligands is regarded as one of the promising strategies to inhibit cancer cell growth. However, recent clinical trials targeting several common cancers showed no beneficial effect when PPAR ligands are used as a monotherapy. Retinoid X receptors (RXRs), which play a critical role in normal cell proliferation as a master regulator for nuclear receptors, preferentially form heterodimers with PPARs. A malfunction of RXRalpha due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of certain types of human malignancies. The activation of PPARgamma/RXR heterodimer by their respective ligands synergistically inhibits cell growth, while inducing apoptosis in human colon cancer cells when the phosphorylation of RXRalpha was inhibited. We herein review the synergistic antitumor effects produced by the combination of the PPAR, especially PPARgamma, ligands plus other agents, especially retinoids, in a variety of human cancers. We also focus on the phosphorylation of RXRalpha because the inhibition of RXRalpha phosphorylation and the restoration of its physiological function may activate PPAR/RXR heterodimer and, therefore, be a potentially effective and critical strategy for the inhibition of cancer cell growth.