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PMID: 18790559 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

PPARgamma-independent antitumor effects of thiazolidinediones.

Cancer letters ·Vol. 276 ·No. 2 ·2009-04-18 ·Pages 119-24

Wei S, Yang J, Lee SL, Kulp SK, Chen CS

Abstract

The thiazolidinedione (TZD) family of PPARgamma 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 PPARgamma activation, 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 PPARgamma-independent antitumor effects, which underscores the translational potential of these agents. Furthermore, dissociation of these antitumor effects from their PPARgamma 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.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Chromans/pharmacology Humans PPAR gamma/physiology Proteasome Endopeptidase Complex/physiology Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors Receptors, Androgen/physiology Signal Transduction Sp1 Transcription Factor/metabolism Thiazolidinediones/pharmacology Troglitazone bcl-X Protein/antagonists & inhibitors
Chemicals
Antineoplastic Agents Chromans PPAR gamma Proto-Oncogene Proteins c-bcl-2 Receptors, Androgen Sp1 Transcription Factor Thiazolidinediones bcl-X Protein Proteasome Endopeptidase Complex Troglitazone ciglitazone
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Wei Shuo
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
Yang Jian
Lee Su-Lin
Kulp Samuel K
Chen Ching-Shih
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41 references, click to expand
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Article Info
Journal
Cancer letters
Abbr.
Cancer Lett
ISSN
1872-7980
DOI
10.1016/j.canlet.2008.08.008
Published
2009-04-18
Epub
2008-00-13
Pages
119-24
Language
English
Region
Ireland
NLM ID
7600053
PMCID
PMC2712818
Subset
IM
Grants
NCI NIH HHS · R21 CA135560-01A1 · United States
NCI NIH HHS · CA 112250 · United States
NCI NIH HHS · R01 CA112250 · United States
NCI NIH HHS · R01 CA112250-04 · United States
NCI NIH HHS · R21 CA135560 · United States
External Links
PubMed source DOI: 10.1016/j.canlet.2008.08.008 PMC Full Text View journal details
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