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[Cancer Research 65, 1561-1569, February 15, 2005]
© 2005 American Association for Cancer Research


Experimental Therapeutics, Molecular Targets and Chemical Biology

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

Chung-Wai Shiau, Chih-Cheng Yang, Samuel K. Kulp, Kuen-Feng Chen, Chang-Shi Chen, Jui-Wen Huang and Ching-Shih Chen

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 {gamma} (PPAR{gamma}) 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{gamma} activation. First, close structural analogues of thiazolidenediones, whereas devoid of PPAR{gamma} activity, retain the ability to induce apoptosis with equal potency. Second, both PC-3 (PPAR{gamma}-expressing) and LNCaP (PPAR{gamma}-deficient) cells are sensitive to apoptosis induction by troglitazone and its PPAR{gamma}-inactive analogue irrespective of their PPAR{gamma} expression status. Third, rosiglitazone and pioglitazone, potent PPAR{gamma} agonists, show marginal effects on apoptosis even at high concentrations. Evidence indicates that the apoptotic effect of troglitazone, ciglitazone, and their PPAR{gamma}-inactive analogues 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy)-benzylidene]-2,4-thiazolidine-dione ({Delta}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 {Delta}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 {Delta}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{gamma}-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 {Delta}2-TG analogue with potent in vivo antitumor activities.

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







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Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2005 by the American Association for Cancer Research.