Abstract
The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in growth and survival of BCR-ABL transformed cells. AMPK kinase is a metabolic sensor that exhibits suppressive effects on the mTOR pathway and negatively regulates mTOR activity. We report that AMPK activators, such as metformin and 5-aminoimidazole-4-carboxamide ribonucleotide, suppress activation of the mTOR pathway in BCR-ABL-expressing cells. Treatment with these inhibitors results in potent suppression of chronic myeloid leukemia leukemic precursors and Ph(+) acute lymphoblastic leukemia cells, including cells expressing the T315I-BCR-ABL mutation. Altogether, our data suggest that AMPK is an attractive target for the treatment of BCR-ABL-expressing malignancies and raise the potential for use of AMPK activators in the treatment of refractory chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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AMP-Activated Protein Kinase Kinases
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Amino Acid Substitution
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Aminoimidazole Carboxamide / analogs & derivatives
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Aminoimidazole Carboxamide / pharmacology
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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Cell Line, Transformed
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Cell Survival / drug effects
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Cell Transformation, Neoplastic / metabolism*
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Down-Regulation / drug effects
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Drug Resistance, Neoplasm
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Enzyme Activation / drug effects
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism*
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Humans
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Leukemia, Lymphoid / drug therapy
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Leukemia, Lymphoid / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / blood
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Metformin / pharmacology
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Molecular Targeted Therapy
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Mutant Proteins / metabolism
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Prodrugs / pharmacology
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Protein Kinases / chemistry*
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Recombinant Proteins / metabolism
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Ribonucleotides / pharmacology
Substances
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Antineoplastic Agents
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Mutant Proteins
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Prodrugs
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Recombinant Proteins
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Ribonucleotides
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Aminoimidazole Carboxamide
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Metformin
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Protein Kinases
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Fusion Proteins, bcr-abl
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AMP-Activated Protein Kinase Kinases
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AICA ribonucleotide