| PPARgamma-independent antitumor effects of thiazolidinediones. | |
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MedLine Citation:
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PMID: 18790559 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Shuo Wei; Jian Yang; Su-Lin Lee; Samuel K Kulp; Ching-Shih Chen |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review Date: 2008-09-13 |
Journal Detail:
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Title: Cancer letters Volume: 276 ISSN: 1872-7980 ISO Abbreviation: Cancer Lett. Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-03-03 Completed Date: 2009-03-20 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 7600053 Medline TA: Cancer Lett Country: Ireland |
Other Details:
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Languages: eng Pagination: 119-24 Citation Subset: IM |
Affiliation:
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Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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* bcl-X Protein / antagonists & inhibitors |
| Grant Support | |
ID/Acronym/Agency:
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CA 112250/CA/NCI NIH HHS; R01 CA112250-04/CA/NCI NIH HHS; R21 CA135560-01A1/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Chromans; 0/PPAR gamma; 0/Proto-Oncogene Proteins c-bcl-2; 0/Receptors, Androgen; 0/Sp1 Transcription Factor; 0/Thiazolidinediones; 0/bcl-X Protein; 74772-77-3/ciglitazone; 97322-87-7/troglitazone; EC 3.4.25.1/Proteasome Endopeptidase Complex |
| Comments/Corrections | |
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