synergistic effects of ppar ligands and retinoids in cancer treatment协同效应的ppar配体,在癌症治疗类维生素a.pdfVIP

Hindawi Publishing Corporation PPAR Research Volume 2008, Article ID 181047, 10 pages doi:10.1155/2008/181047 Review Article Synergistic Effects of PPARγ Ligands and Retinoids in Cancer Treatment Masahito Shimizu and Hisataka Moriwaki Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan Correspondence should be addressed to Masahito Shimizu, shimim-gif@umin.ac.jp Received 26 February 2008; Revised 21 April 2008; Accepted 1 May 2008 Recommended by Dipak Panigrahy 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 RXRα due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of certain types of human malignancies. The activation of PPARγ/RXR heterodimer by their respective ligands synergistically inhibits cell growth, while inducing apoptosis in human colon cancer cells when the phosphorylation of RXRα was inhibited. We herein review the synergistic antitumor effects produced by the combination of the PPAR, especially PPARγ, ligands plus other agents, especially retinoids, in a variety of human cancers. We also focus on the phosphorylation of RXRα because the inhibition of RXRα phosphorylation and the restoration of its physiological function may activate PPAR/RXR heterodimer and, therefore