Abstract |
Recently, strategies for acute myeloid leukemia (AML) therapy have been developed that target anti-apoptotic BCL2 family members using BH3-mimetic drugs such as ABT-737. Though effective against BCL2 and BCL-X(L), ABT-737 poorly inhibits MCL-1. Here we report that, unexpectedly, ABT-737 induces activation of the extracellular receptor activated kinase and induction of MCL-1 in AML cells. MEK inhibitors such as PD0325901 and CI-1040 have been used successfully to suppress MCL-1. We report that PD0325901 blocked ABT-737-induced MCL-1 expression, and when combined with ABT-737 resulted in potent synergistic killing of AML-derived cell lines, primary AML blast and CD34+38-123+ progenitor/stem cells. Finally, we tested the combination of ABT-737 and CI-1040 in a murine xenograft model using MOLM-13 human leukemia cells.Whereas control mice and CI-1040-treated mice exhibited progressive leukemia growth, ABT-737, and to a significantly greater extent, ABT-737+CI-1040 exerted major anti- leukemia activity. Collectively, results demonstrated unexpected anti-apoptotic interaction between the BCL2 family-targeted BH3-mimetic ABT-737 and mitogen-activated protein kinase signaling in AML cells: the BH3 mimetic is not only restrained in its activity by MCL-1, but also induces its expression. However, concomitant inhibition by BH3 mimetics and MEK inhibitors could abrogate this effect and may be developed into a novel and effective therapeutic strategy for patients with AML.
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Authors | M Konopleva, M Milella, P Ruvolo, J C Watts, M R Ricciardi, B Korchin, T McQueen, W Bornmann, T Tsao, P Bergamo, D H Mak, W Chen, J McCubrey, A Tafuri, M Andreeff |
Journal | Leukemia
(Leukemia)
Vol. 26
Issue 4
Pg. 778-87
(Apr 2012)
ISSN: 1476-5551 [Electronic] England |
PMID | 22064351
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- ABT-737
- Antineoplastic Agents
- Apoptosis Regulatory Proteins
- BAK1 protein, human
- BCL2L11 protein, human
- Bcl-2-Like Protein 11
- Bcl2l11 protein, mouse
- Benzamides
- Biphenyl Compounds
- Mcl1 protein, mouse
- Membrane Proteins
- Myeloid Cell Leukemia Sequence 1 Protein
- Nitrophenols
- Piperazines
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-bcl-2
- Sulfonamides
- bcl-2 Homologous Antagonist-Killer Protein
- bcl-2-Associated X Protein
- mirdametinib
- Diphenylamine
- Extracellular Signal-Regulated MAP Kinases
- Mitogen-Activated Protein Kinase Kinases
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Apoptosis Regulatory Proteins
(metabolism)
- Bcl-2-Like Protein 11
- Benzamides
(pharmacology)
- Biphenyl Compounds
(pharmacology)
- Cell Line, Tumor
- Diphenylamine
(analogs & derivatives, pharmacology)
- Extracellular Signal-Regulated MAP Kinases
(physiology)
- Humans
- Leukemia, Myeloid, Acute
(drug therapy, metabolism, pathology)
- Membrane Proteins
(metabolism)
- Mice
- Mice, Nude
- Mitogen-Activated Protein Kinase Kinases
(antagonists & inhibitors)
- Myeloid Cell Leukemia Sequence 1 Protein
- Nitrophenols
(pharmacology)
- Piperazines
(pharmacology)
- Proto-Oncogene Proteins
(metabolism)
- Proto-Oncogene Proteins c-bcl-2
(analysis, antagonists & inhibitors, metabolism)
- Sulfonamides
(pharmacology)
- bcl-2 Homologous Antagonist-Killer Protein
(metabolism)
- bcl-2-Associated X Protein
(physiology)
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