Antileukemic effects of AMPK activators on BCR-ABL-expressing cells.
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.
Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA.
Eliza
E
Vakana
Jessica K
JK
Altman
Heather
H
Glaser
Nicholas J
NJ
Donato
Leonidas C
LC
Platanias
D000091162:AMP-Activated Protein Kinase Kinases; D019943:Amino Acid Substitution; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry*; D011994:Recombinant Proteins / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology
D000970:Antineoplastic Agents; D050505:Mutant Proteins; D011355:Prodrugs; D011994:Recombinant Proteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D011494:Protein Kinases; D016044:Fusion Proteins, bcr-abl; D000091162:AMP-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide