The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia.
In acute myeloid leukemia (AML), resistance to chemotherapy is associated with defects in both the extrinsic and intrinsic pathways of apoptosis. Novel agents that activate endogenous apoptosis-inducing mechanisms directly may be potentially useful to overcome chemoresistance in AML. We examined the mechanisms of apoptosis induction by the novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) in AML cells. CDDO-induced apoptosis was associated with the loss of mitochondrial inner transmembrane potential, caspases activation, the translocation of apoptosis-inducing factor to the nucleus, and DNA fragmentation in AML cells. Apoptosis was equally evident in cells deficient in caspase-9 or caspase-8 after exposure to CDDO, suggesting caspase-independent cell death. The use of small interfering RNA to reduce the expression of apoptosis-inducing factor partially inhibited CDDO-induced apoptosis in AML cells. Cells overexpressing Bcl-2 were markedly resistant to CDDO-induced apoptosis. Moreover, CDDO promoted the release of cytochrome c from isolated mitochondria, suggesting that CDDO targets the mitochondria directly to trigger the intrinsic pathway of cell death in intact cells. Together, these results suggest that CDDO functions by activating the intrinsic pathway of apoptosis and initiates caspase-dependent and independent cell death. The direct modulation of mitochondrial-mediated, caspase-independent apoptosis by CDDO may be advantageous for overcoming chemoresistance in AML.
Konopleva
Marina
M
Section of Molecular Hematology and Therapy and the Department of Blood and Marrow Transplantation at The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Tsao
Twee
T
Estrov
Zeev
Z
Lee
Ruey-min
RM
Wang
Rui-Yu
RY
Jackson
C Ellen
CE
McQueen
Teresa
T
Monaco
Giuseppe
G
Munsell
Mark
M
Belmont
John
J
Kantarjian
Hagop
H
Sporn
Michael B
MB
Andreeff
Michael
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor; D020169:Caspases / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005420:Flavoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D047495:PPAR gamma / Q000502:physiology; D010718:Phosphatidylserines / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; D047495:PPAR gamma; D010718:Phosphatidylserines; D019253:Proto-Oncogene Proteins c-bcl-2; D009828:Oleanolic Acid; D020169:Caspases