Treatment results for acute myeloid leukemia's (AML) have not changed for over two decades, except for the improved response rates and survival of patients with acute promyelocytic leukemia treated with all-transretinoic acid. 2-Cyano-3,12-Dioxoolean-1,9-Dien-28-Oic Acid (CDDO) is a novel triterpenoid with unique properties: it induces differentiation, inhibits cell growth and induces apoptosis in leukemia cell lines and in primary samples from patients with AML and blast transformation of CML. CDDO ligates and transcaptivates the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), which forms heterodimers with the retinoid X receptor (RXR). We here propose to extend our initial studies on the efficacy and mechanisms of CDDO activity in AML, with the goal of developing CDDO as a drug for the treatment of hematological malignancies. First, we will further investigate the growth-inhibitory effects of CDDO on primary AML and normal hematopoietic progenitors in suspension and clonogenic assay systems. Second, we will define the effects of CDDO on the transcriptional function of PPARgamma, which we found to be highly expressed in AML. Third, we will elucidate mechanisms of apoptotic cell death and growth arrest downstream from CDDO-induced PPARgamma ligation. Preliminary data demonstrate that CDDO induces loss of mitochondrial membrane potential and activation of caspases. Finally, we will conduct in vivo experiments in the NOD/Scid model of AML. The long-term goal of our proposed mechanistic and efficacy studies is to determine the potential of CDDO as a novel anti-leukemia and anti-tumor agent.
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