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PPAR Research
Volume 2012 (2012), Article ID 269751, 16 pages
http://dx.doi.org/10.1155/2012/269751
Research Article

AS601245, an Anti-Inflammatory JNK Inhibitor, and Clofibrate Have a Synergistic Effect in Inducing Cell Responses and in Affecting the Gene Expression Profile in CaCo-2 Colon Cancer Cells

1MerckSerono Ivrea, Istituto di Ricerche Biomediche “A. Marxer”, RBM S.p.A., 10010 Colleretto Giacosa, Italy
2Department of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, Italy
3Department of Anatomy, Pharmacology and Forensic Medicine, Section of Pharmacology and Pharmacognosy, University of Turin,10125 Turin, Italy
4Department of Anatomy, Pharmacology, and Forensic Medicine, Section of Pharmacology and Experimental Therapy, University of Turin, 10125 Turin, Italy

Received 2 August 2011; Revised 29 October 2011; Accepted 1 November 2011

Academic Editor: J. Reddy

Copyright © 2012 Angelo Cerbone et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

PPARαs are nuclear receptors highly expressed in colon cells. They can be activated by the fibrates (clofibrate, ciprofibrate etc.) used to treat hyperlipidemia. Since PPARα transcriptional activity can be negatively regulated by JNK, the inhibition of JNK activity could increase the effectiveness of PPARα ligands. We analysed the effects of AS601245 (a JNK inhibitor) and clofibrate alone or in association, on proliferation, apoptosis, differentiation and the gene expression profile of CaCo-2 human colon cancer cells. Proliferation was inhibited in a dose-dependent way by clofibrate and AS601245. Combined treatment synergistically reduced cell proliferation, cyclin D1 and PCNA expression and induced apoptosis and differentiation. Reduction of cell proliferation, accompanied by the modulation of p21 expression was observed in HepG2 cells, also. Gene expression analysis revealed that some genes were highly modulated by the combined treatment and 28 genes containing PPRE were up-regulated, while clofibrate alone was ineffective. Moreover, STAT3 signalling was strongly reduced by combined treatment. After combined treatment, the binding of PPARα to PPRE increased and paralleled with the expression of the PPAR coactivator MED1. Results demonstrate that combined treatment increases the effectiveness of both compounds and suggest a positive interaction between PPARα ligands and anti-inflammatory agents in humans.