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.
The initial success of the first synthetic bcr-abl kinase inhibitor imatinib has been dampened by the emergence of imatinib-resistant disease in blast crisis chronic myeloid leukemia. Here, we report that the novel triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate (CDDO-Me) potently induced cytotoxicity in imatinib-resistant KBM5 cells expressing the T315I mutation of bcr-abl (24-h EC50, 540 nmol/L). In long-term culture, CDDO-Me abrogated the growth of human parental KBM5 and KBM5-STI cells with 96-h IC50 of 205 and 221 nmol/L, respectively. In addition, CDDO-Me rapidly decreased the viability of murine lymphoid Ba/F3 cells expressing wild-type p210 as well as the imatinib-resistant E255K and T315I mutations of bcr-abl. The low-dose effects of CDDO-Me are associated with inhibition of mitochondrial oxygen consumption, whereas the cytotoxic effects appear to be mediated by a rapid and selective depletion of mitochondrial glutathione that accompanies the increased generation of reactive oxygen species and mitochondrial dysfunction. Interestingly, the mitochondriotoxic effects of CDDO-Me are followed by the rapid autophagocytosis of intracellular organelles or the externalization of phosphatidylserine in different cell types. We conclude that alterations in mitochondrial function by CDDO-Me can result in autophagy or apoptosis of chronic myeloid leukemia cells regardless of the mutational status of bcr-abl. CDDO-Me is in clinical trials and shows signs of clinical activity, with minimal side effects and complete lack of cardiotoxicity. Studies in leukemias are in preparation.
Samudio
Ismael
I
Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Kurinna
Svitlana
S
Ruvolo
Peter
P
Korchin
Borys
B
Kantarjian
Hagop
H
Beran
Miloslav
M
Dunner
Kenneth
K
Kondo
Seiji
S
Andreeff
Michael
M
Konopleva
Marina
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001343:Autophagy; D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid; D000068877:Imatinib Mesylate; C445068:bardoxolone methyl; D016044:Fusion Proteins, bcr-abl; D010100:Oxygen