Journal
PPAR RESEARCH
Volume 2008, Issue -, Pages -Publisher
HINDAWI LTD
DOI: 10.1155/2008/494161
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Funding
- Thomas and Agnes Carvel Foundation
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PPAR gamma is a therapeutic target that has been exploited for treatment of type II diabetes mellitus (T2DM) with agonist drugs. Since PPAR gamma is expressed by many hematopoietic, mesodermal and epithelial cancers, agonist drugs were tested and shown to have both preclinical and clinical anticancer activity. While preclinical activity has been observed in many cancer types, clinical activity has been observed only in pilot and phase II trials in liposarcoma and prostate cancer. Most studies address agonist compounds, with substantially fewer reports on anticancer effects of PPAR gamma antagonists. In cancer model systems, some effects of PPAR gamma agonists were not inhibited by PPAR gamma antagonists, suggesting noncanonical or PPAR gamma-independent mechanisms. In addition, PPAR gamma antagonists, such as T0070907 and GW9662, have exhibited antiproliferative effects on a broad range of hematopoietic and epithelial cell lines, usually with greater potency than agonists. Also, additive antiproliferative effects of combinations of agonist plus antagonist drugs were observed. Finally, there are preclinical in vivo data showing that antagonist compounds can be administered safely, with favorable metabolic effects as well as antitumor effects. Since PPAR gamma antagonists represent a new drug class that holds promise as a broadly applicable therapeutic approach for cancer treatment, it is the subject of this review. Copyright (C) 2008 Jack D. Burton et al.
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