PPARgamma-independent antitumor effects of thiazolidinediones.
PPARgamma-independent antitumor effects of thiazolidinediones.
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DOI：
10.1016/j.canlet.2008.08.008
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发表时间：
2009-04-18
期刊：
影响因子：
9.7
通讯作者：
Chen, Ching-Shih
中科院分区：
文献类型：
--
作者：
Wei, Shuo;Yang, Jian;Lee, Su-Lin;Kulp, Samuel K.;Chen, Ching-Shih
关键词：
The thiazolidinedione (TZD) family of PPARγ agonists, especially troglitazone and ciglitazone, induce cell cycle arrest, differentiation, and apoptosis in cancer cells. Mounting evidence indicates that TZDs interfere with multiple signaling mechanisms independently of PPARγactivation, which affect many aspects of cellular functions governing cell cycle progression and survival of cancer cells. Here, we review the “off-target” mechanisms that underlie the antitumor effects of TZDs with emphasis on three key pathways, namely, inhibition of Bcl-2/Bcl-xL function, proteasomal degradation of cell cycle- and apoptosis-regulatory proteins, and transcriptional repression of androgen receptor (AR) through Sp1 degradation. Relative to tumor cells, nonmalignant cells are resistant to these PPARγ-independent antitumor effects, which underscores the translational potential of these agents. Furthermore, dissociation of these antitumor effects from their PPARγ agonist activity provides a rationale for using TZDs as scaffolds for lead optimization to develop a novel class of antitumor agents with a unique mode of mechanism.
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