Peroxisome proliferator-activated receptor ; and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias

The peroxisome proliferator-activated receptor ; (PPAR;) is a member of the nuclear receptor family that forms heterodimers with retinoid X receptor. These heterodimers bind to DNA and activate the transcription of target genes. Here, we report that the PPAR; receptor protein is expressed in primary myeloid and lymphoid leukemias and in lymphoma and myeloma cell lines. In this study, we compared the activity of several PPAR; ligands including BRL49653 (rosiglitazone), 15-deoxy-#12,14-prostaglandin J2, and the novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid on leukemia cells. Exposure to these PPAR; ligands induced apoptosis in myeloid (U937 and HL-60) and lymphoid (Su-DHL, Sup-M2, Ramos, Raji, Hodgkin’s cell lines, and primary chronic lymphocytic leukemia) cells. A similar exposure to these PPAR; ligands induced the differentiation of myeloid leukemic cells. A combination of PPAR; ligands with a retinoid X receptor agonist (i.e., LG100268) or a retinoic acid receptor agonist (i.e., all trans-retinoic acid) enhanced differentiating and growth-inhibitory effects. 2-Cyano-3,12-dioxooleana-1,9dien-28-oic acid induced differentiation and apoptosis with much greater potency than the other PPAR; ligands in established cell lines and primary chronic lymphocytic leukemia samples. Exposure to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induced mitochondrial depolarization and caspase activation, which was associated with apoptosis induction. In Bcl-2-overexpressing chronic lymphocytic leukemia cells, the small-molecule Bcl-2 inhibitor HA14-1 sensitized these cells to 2-cyano-3,12dioxooleana-1,9-dien-28-oic acid– induced apoptosis. These results suggest that PPAR; ligation alone and in combination with retinoids holds promise as novel therapy for leukemias by activating the transcriptional activity of target genes that control apoptosis and differentiation in leukemias. [Mol Cancer Ther 2004;3(10):1249–62]