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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089346-03
Application #
6796771
Study Section
Special Emphasis Panel (ZRG1-ET-2 (05))
Program Officer
Fu, Yali
Project Start
2002-09-01
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$251,815
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Kojima, Kensuke; Burks, Jared K; Arts, Janine et al. (2010) The novel tryptamine derivative JNJ-26854165 induces wild-type p53- and E2F1-mediated apoptosis in acute myeloid and lymphoid leukemias. Mol Cancer Ther 9:2545-57
Kojima, Kensuke; Shimanuki, Masaya; Shikami, Masato et al. (2009) Cyclin-dependent kinase 1 inhibitor RO-3306 enhances p53-mediated Bax activation and mitochondrial apoptosis in AML. Cancer Sci 100:1128-36
Kojima, Kensuke; Konopleva, Marina; Tsao, Twee et al. (2008) Concomitant inhibition of Mdm2-p53 interaction and Aurora kinases activates the p53-dependent postmitotic checkpoints and synergistically induces p53-mediated mitochondrial apoptosis along with reduced endoreduplication in acute myelogenous leukemia. Blood 112:2886-95
Kong, G; Wang, D; Wang, H et al. (2008) Synthetic triterpenoids have cytotoxicity in pediatric acute lymphoblastic leukemia cell lines but cytotoxicity is independent of induced ceramide increase in MOLT-4 cells. Leukemia 22:1258-62
Samudio, Ismael; Kurinna, Svitlana; Ruvolo, Peter et al. (2008) Inhibition of mitochondrial metabolism by methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate induces apoptotic or autophagic cell death in chronic myeloid leukemia cells. Mol Cancer Ther 7:1130-9
Tabe, Yoko; Konopleva, Marina; Kondo, Yutaka et al. (2007) PPARgamma-active triterpenoid CDDO enhances ATRA-induced differentiation in APL. Cancer Biol Ther 6:1967-77
Kress, Christina L; Konopleva, Marina; Martinez-Garcia, Vanesa et al. (2007) Triterpenoids display single agent anti-tumor activity in a transgenic mouse model of chronic lymphocytic leukemia and small B cell lymphoma. PLoS One 2:e559
Koschmieder, Steffen; D'Alo, Francesco; Radomska, Hanna et al. (2007) CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha. Blood 110:3695-705
Milella, Michele; Konopleva, Marina; Precupanu, Cristina M et al. (2007) MEK blockade converts AML differentiating response to retinoids into extensive apoptosis. Blood 109:2121-9
Kojima, Kensuke; Konopleva, Marina; Samudio, Ismael J et al. (2007) Mitogen-activated protein kinase kinase inhibition enhances nuclear proapoptotic function of p53 in acute myelogenous leukemia cells. Cancer Res 67:3210-9

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