title: PPARgamma-independent antitumor effects of thiazolidinediones.
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.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wei
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Su-Lin
authors.initials: SL
authors.lastname: Lee
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology; D006801:Humans; D047495:PPAR gamma / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011944:Receptors, Androgen / Q000502:physiology; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D011944:Receptors, Androgen; D016329:Sp1 Transcription Factor; D045162:Thiazolidinediones; D051020:bcl-X Protein; D046988:Proteasome Endopeptidase Complex; D000077288:Troglitazone; C039671:ciglitazone
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