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PPAR Research
Volume 2008 (2008), Article ID 256251, 10 pages
http://dx.doi.org/10.1155/2008/256251
Review Article

Mitochondria, PPARs, and Cancer: Is Receptor-Independent Action of PPAR Agonists a Key?

Department of Laboratory Medicine, Catholic University, Largo A. Gemelli 8, 00168 Rome, Italy

Received 26 March 2008; Revised 27 May 2008; Accepted 18 June 2008

Academic Editor: Dipak Panigrahy

Copyright © 2008 Roberto Scatena 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

Before the discovery of peroxisome proliferator activated receptors (PPARs), it was well known that certain drugs considered as classical PPAR-alpha agonists induced hepatocarcinoma or peroxisome proliferation in rodents. These drugs were derivatives of fibric acid, and they included clofibrate, bezafibrate, and fenofibrate. However, such toxicity has never been observed in human patients treated with these hypolipidemic drugs. Thiazolidinediones are a new class of PPAR activators showing greater specificity for the 𝛾 isoform of PPARs. These drugs are used as insulin sensitizers in the treatment of type II diabetes. In addition, they have been shown to induce cell differentiation or apoptosis in various experimental models of cancer. PPAR- 𝛼 ligands have also been shown to induce cancer cell differentiation and, paradoxically, PPAR- 𝛾 drug activators have been reported to act as carcinogens. The confusing picture that emerges from these data is further complicated by the series of intriguing side effects observed following administration of pharmacological PPAR ligands (rhabdomyolysis, liver and heart toxicity, anemia, leucopenia). These side effects cannot be easily explained by simple interactions between the drug and nuclear receptors. Rather, these side effects seem to indicate that the ligands have biological activity independent of the nuclear receptors. Considering the emerging role of mitochondria in cancer and the potential metabolic connections between this organelle and PPAR physiology, characterization of the reciprocal influences is fundamental not only for a better understanding of cancer biology, but also for more defined pharmacotoxicological profiles of drugs that modulate PPARs.