Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia.
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.
Konopleva
Marina
M
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.
Tsao
Twee
T
Ruvolo
Peter
P
Stiouf
Irina
I
Estrov
Zeev
Z
Leysath
Clinton E
CE
Zhao
Shourong
S
Harris
David
D
Chang
Shirong
S
Jackson
C Ellen
CE
Munsell
Mark
M
Suh
Nanjoo
N
Gribble
Gordon
G
Honda
Tadashi
T
May
W Stratford
WS
Sporn
Michael B
MB
Andreeff
Michael
M
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
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