gw9662 and Multiple-Myeloma

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.

Topics: Anilides; Antineoplastic Agents; Apoptosis; Benzamides; Carcinoma; Caspase Inhibitors; Caspases; Cell Line, Tumor; Cell Proliferation; Hematologic Neoplasms; Humans; Indicators and Reagents; Interleukin-6; Multiple Myeloma; Pioglitazone; PPAR gamma; Pyridines; Thiazolidinediones

Multiple myeloma (MM) remains largely incurable despite conventional and high-dose therapies. Therefore, novel biologically based treatment approaches are urgently required. Here we demonstrate that expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in MM cells and its agonists 15-d-PGJ2 and troglitazone completely abolished IL-6-inducible MM cell proliferation and induced apoptosis through affecting expression of multiple cell cycle or apoptosis genes, whereas PPARgamma antagonist GW9662 and PPARalpha agonist WY14643 did not display this inhibitory effect. These PPARgamma agonists significantly inhibited DNA binding and transactivation of STAT3 bound to the promoter of target genes in chromatin, but did not affect the expression of IL-6 receptor and phosphorylation of JAK/STAT3, MAPK, and PI3K/Akt. Interestingly, although inactivation of STAT3 by PPARgamma agonists is in a PPARgamma-dependent manner, the molecular mechanism by which two structurally distinct PPARgamma agonists suppress IL-6-activated STAT3 shows the divergent interactions between PPARgamma and STAT3 including direct or SMRT-mediated association.

Topics: Anilides; Antineoplastic Agents; Apoptosis; Blotting, Western; Bone Marrow Cells; Cell Division; Cells, Cultured; Chromans; DNA-Binding Proteins; Down-Regulation; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Gene Expression; Humans; Interleukin-6; Multiple Myeloma; Peroxisome Proliferators; Precipitin Tests; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor; Thiazolidinediones; Trans-Activators; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transfection; Troglitazone