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Thiazolidenediones Mediate Apoptosis in Prostate Cancer Cells in Part through Inhibition of Bcl-xL/Bcl-2 Functions Independently of PPAR

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, Ohio

Requests for reprints: Ching-Shih Chen, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Room 336, Parks Hall, 500 West 12th Avenue, Columbus, OH 43210. Phone: 614-688-4008; Fax: 614-688-8556; E-mail: chen.844{at}osu.edu.

Certain members of the thiazolidenedione family of the peroxisome proliferator-activated receptor (PPAR) agonists, such as troglitazone and ciglitazone, exhibit antitumor effects; however, the underlying mechanism remains inconclusive. This study shows that the effect of these thiazolidenedione members on apoptosis in prostate cancer cells is independent of PPAR activation. First, close structural analogues of thiazolidenediones, whereas devoid of PPAR activity, retain the ability to induce apoptosis with equal potency. Second, both PC-3 (PPAR-expressing) and LNCaP (PPAR-deficient) cells are sensitive to apoptosis induction by troglitazone and its PPAR-inactive analogue irrespective of their PPAR expression status. Third, rosiglitazone and pioglitazone, potent PPAR agonists, show marginal effects on apoptosis even at high concentrations. Evidence indicates that the apoptotic effect of troglitazone, ciglitazone, and their PPAR-inactive analogues 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy)-benzylidene]-2,4-thiazolidine-dione (2-TG) and 5-[4-(1-methyl-cyclohexylmethoxy)-benzylidene]-thiazolidine-2,4-dione, respectively, is in part attributable to their ability to inhibit the anti-apoptotic functions of Bcl-xL and Bcl-2. Treatment of PC-3 cells with troglitazone or 2-TG led to reduced association of Bcl-2 and Bcl-xL with Bak, leading to caspase-dependent apoptosis. Bcl-xL overexpression protects LNCaP cells from apoptosis induction by troglitazone and 2-TG in an expression level–dependent manner. Considering the pivotal role of Bcl-xL/Bcl-2 in regulating mitochondrial integrity, this new mode of mechanism provides a framework to account for the PPAR-independent action of thiazolidenediones in inducing apoptosis in cancer cells. Moreover, dissociation of these two pharmacologic activities provides a molecular basis to develop novel Bcl-xL/Bcl-2 inhibitors, of which the proof of principle is illustrated by a 2-TG analogue with potent in vivo antitumor activities.

Key Words: PPAR agonists • troglitazone • apoptosis • Bcl-xL • Bcl-2

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