Antileukemic effects of AMPK activators on BCR-ABL-expressing cells

Blood. 2011 Dec 8;118(24):6399-402. doi: 10.1182/blood-2011-01-332783. Epub 2011 Oct 21.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Amino Acid Substitution
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Cell Line, Transformed
  • Cell Survival / drug effects
  • Cell Transformation, Neoplastic / metabolism*
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm
  • Enzyme Activation / drug effects
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Leukemia, Lymphoid / drug therapy
  • Leukemia, Lymphoid / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / blood
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Metformin / pharmacology
  • Molecular Targeted Therapy
  • Mutant Proteins / metabolism
  • Prodrugs / pharmacology
  • Protein Kinases / chemistry*
  • Recombinant Proteins / metabolism
  • Ribonucleotides / pharmacology

Substances

  • Antineoplastic Agents
  • Mutant Proteins
  • Prodrugs
  • Recombinant Proteins
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Metformin
  • Protein Kinases
  • Fusion Proteins, bcr-abl
  • AMP-Activated Protein Kinase Kinases
  • AICA ribonucleotide