title: Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia.
abstract: It has been shown that the novel synthetic triterpenoid CDDO inhibits proliferation and induces differentiation and apoptosis in myeloid leukemia cells. In the current study the effects of the C-28 methyl ester of CDDO, CDDO-Me, were analyzed on cell growth and apoptosis of leukemic cell lines and primary acute myelogenous leukemia (AML). CDDO-Me decreased the viability of leukemic cell lines, including multidrug resistant (MDR)-1-overexpressing, p53(null) HL-60-Dox and of primary AML cells, and it was 3- to 5-fold more active than CDDO. CDDO-Me induced a loss of mitochondrial membrane potential, induction of caspase-3 cleavage, increase in annexin V binding and DNA fragmentation, suggesting the induction of apoptosis. CDDO-Me induced pro-apoptotic Bax protein that preceded caspase activation. Furthermore, CDDO-Me inhibited the activation of ERK1/2, as determined by the inhibition of mitochondrial ERK1/2 phosphorylation, and it blocked Bcl-2 phosphorylation, rendering Bcl-2 less anti-apoptotic. CDDO-Me induced granulo-monocytic differentiation in HL-60 cells and monocytic differentiation in primary cells. Of significance, colony formation of AML progenitors was significantly inhibited in a dose-dependent fashion, whereas normal CD34(+) progenitor cells were less affected. Combinations with ATRA or the RXR-specific ligand LG100268 enhanced the effects of CDDO-Me on cell viability and terminal differentiation of myeloid leukemic cell lines. In conclusion, CDDO-Me is an MDR-1- and a p53-independent compound that exerts strong antiproliferative, apoptotic, and differentiating effects in myeloid leukemic cell lines and in primary AML samples when given in submicromolar concentrations. Differential effects of CDDO-Me on leukemic and normal progenitor cells suggest that CDDO-Me has potential as a novel compound in the treatment of hematologic malignancies.
authors.affiliation: Department of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Twee
authors.initials: T
authors.lastname: Tsao
authors.forename: Peter
authors.initials: P
authors.lastname: Ruvolo
authors.forename: Irina
authors.initials: I
authors.lastname: Stiouf
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Clinton E
authors.initials: CE
authors.lastname: Leysath
authors.forename: Shourong
authors.initials: S
authors.lastname: Zhao
authors.forename: David
authors.initials: D
authors.lastname: Harris
authors.forename: Shirong
authors.initials: S
authors.lastname: Chang
authors.forename: C Ellen
authors.initials: CE
authors.lastname: Jackson
authors.forename: Mark
authors.initials: M
authors.lastname: Munsell
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
authors.forename: Gordon
authors.initials: G
authors.lastname: Gribble
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
authors.forename: W Stratford
authors.initials: WS
authors.lastname: May
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001752:Blast Crisis / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004347:Drug Interactions; D005434:Flow Cytometry; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
chemical_list: C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D017304:Annexin A5; C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012176:Retinoids; D051028:bcl-2-Associated X Protein; D003561:Cytarabine; D014212:Tretinoin; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases