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

• Chung-Wai Shiau

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

• Chih-Cheng Yang

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

• Samuel K. Kulp

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

• Kuen-Feng Chen

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

• Chang-Shi Chen

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

• Jui-Wen Huang

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

• Ching-Shih Chen

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

抄録

Certain members of the thiazolidenedione family of the peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ activation. First, close structural analogues of thiazolidenediones, whereas devoid of PPARγ activity, retain the ability to induce apoptosis with equal potency. Second, both PC-3 (PPARγ-expressing) and LNCaP (PPARγ-deficient) cells are sensitive to apoptosis induction by troglitazone and its PPARγ-inactive analogue irrespective of their PPARγ expression status. Third, rosiglitazone and pioglitazone, potent PPARγ agonists, show marginal effects on apoptosis even at high concentrations. Evidence indicates that the apoptotic effect of troglitazone, ciglitazone, and their PPARγ-inactive analogues 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy)-benzylidene]-2,4-thiazolidine-dione (Δ2-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 Δ2-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 Δ2-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 PPARγ-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 Δ2-TG analogue with potent in vivo antitumor activities.

収録刊行物

• Cancer Research

  Cancer Research 65 (4), 1561-1569, 2005-02-15

  American Association for Cancer Research (AACR)

キーワード

• Cancer Research
• Oncology

詳細情報

• CRID: 1361137044708854912
• NII論文ID: 30018588668
• DOI: 10.1158/0008-5472.can-04-1677
• ISSN: 15387445
• ISSN: 00085472
• Web Site: https://aacrjournals.org/cancerres/article-pdf/65/4/1561/2539852/1561-1569.pdf
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