Peroxisome proliferators as differentiating agents: an intriguing mechanism of action.

R Scatena, MD,G Nocca, PhD, P Bottoni, PhD, I Messana, PhD, F Vincenzoni, PhD, L Ceccarelli, B Giardina, PhD.

Institute of Biochemistry and Clinical Biochemistry. Catholic University, Largo A. Gemelli, 8 00168- Rome, Italy.

AIM. PPARs (peroxisome proliferator activated receptors) showed antiproliferative effect in several malignant cell types, suggesting that their ligands may prove valuable as antitumor agents. Interestingly well-known peroxisome-proliferating chemicals produce a myriad of extraperoxisomal effects in different tissues independently by PPARs interaction; suggesting that metabolic and differentiating/antitumor effects of these compounds could not be totally depending on PPAR activation. Analysis of mechanisms of action of different peroxisome-proliferator could clarify some molecular events related to differentiation/dedifferentiation processes. METHODS. Human acute promyelocytic leukaemia HL-60 cell line and human rhabdomiosarcoma TE-671 cell line were cultured in media containing different PPARs ligands. Spectrophotometric analysis of mitochondrial respiratory chain enzymes, NMR metabolite determinations, PPARs expression by RT-PCR and PCR and cytochemical and functional differentiation assays were adopted. RESULTS. All tested compounds caused: i) a selective derangement of mitochondrial respiratory chain which resulted in morphological alterations and intriguing metabolic compensatory mechanisms; ii) a significant inhibition of cell growth and clear evidences of cell differentiation not related to PPARs expression CONCLUSIONS. Differentiating activity of peroxisome proliferators could give a new light on the pathophysiology of the dedifferentiation process. On the basis of the results, we are faced with the following aspects of therapeutic potential of PPARs ligands: · The compensatory machinery implicated in the maintenance of cellular homeostasis and its role in promoting the differentiation state; · The role of this particular class of differentiating factors in a new definition of dedifferentiation/differentiation processes in cancer.

KEY WORDS: mitochondria, differentiation, cancer, diabetes, atherosclerosis, PPARs.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Therapies, Part 1.