title: Peroxisome proliferator-activated receptor-gamma antagonists exhibit potent antiproliferative effects versus many hematopoietic and epithelial cancer cell lines.
abstract: Peroxisome proliferator-activated receptor-gamma ligands have preclinical and clinical anticancer activity. Most studies in this area address agonists, with relatively few reports on anticancer effects of peroxisome proliferator-activated receptor-gamma antagonists. Thus, we evaluated the two pure peroxisome proliferator-activated receptor-gamma antagonists, T0070907 and GW9662, on a panel of hematopoietic and epithelial cell lines. The peroxisome proliferator-activated receptor-gamma antagonists and a reference agonist (pioglitazone) were tested in an in-vitro proliferation assay on a panel of seven hematopoietic and nine epithelial cancer cell lines, some of which are chemoresistant. Peroxisome proliferator-activated receptor-gamma expression was measured by immunoblotting, as was the effect of treatment with these agents on peroxisome proliferator-activated receptor-gamma levels. The effect of exogenous interleukin-6, an antiapoptotic cytokine, on growth inhibition was evaluated as well as the apoptotic effects of these drugs. The peroxisome proliferator-activated receptor-gamma antagonists showed significantly greater potency on all cell lines (IC50s of 3.2-29.7 versus 26.5-78.7 micromol/l for pioglitazone) and greater maximum growth inhibition. Peroxisome proliferator-activated receptor-gamma levels did not correlate with growth inhibition in this panel of cell lines. Combinations of peroxisome proliferator-activated receptor-gamma antagonists and the agonist actually showed schedule-dependent increases in growth inhibition. Exogenous interleukin-6 did not induce resistance to these agents. Both the antagonists and the agonist induced apoptosis, but only the former drugs showed caspase dependence. These two peroxisome proliferator-activated receptor-gamma antagonists have significantly more potent in-vitro antiproliferative effects versus hematopoietic and epithelial cancer cell lines. This effect does not correlate with peroxisome proliferator-activated receptor-gamma levels, suggesting alternative mechanisms or other targets of action. These findings support further translational studies to explore the mechanism of action and therapeutic potential of this class of agents.
authors.affiliation: Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109, USA. jburton@gscancer.org
authors.forename: Jack D
authors.initials: JD
authors.lastname: Burton
authors.forename: Mary E
authors.initials: ME
authors.lastname: Castillo
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: Rosalyn D
authors.initials: RD
authors.lastname: Blumenthal
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007202:Indicators and Reagents; D015850:Interleukin-6 / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D000077205:Pioglitazone; D011725:Pyridines / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; D061945:Caspase Inhibitors; D007202:Indicators and Reagents; D015850:Interleukin-6; D047495:PPAR gamma; D011725:Pyridines; C458508:T 0070907; D045162:Thiazolidinediones; D020169:Caspases; D000077205:Pioglitazone