Cytotoxic effect of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) on childhood acute lymphoblastic leukemia (ALL) cells: implication for targeted therapy

Mol Cancer. 2007 Jul 10;6:46. doi: 10.1186/1476-4598-6-46.

Abstract

Background: Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy affecting children. Despite significant progress and success in the treatment of ALL, a significant number of children continue to relapse and for them, outcome remains poor. Therefore, the search for novel therapeutic approaches is warranted. The aim of this study was to investigate the AMP activated protein kinase (AMPK) as a potential target in childhood acute lymphoblastic leukemia (ALL) subtypes characterized by non-random translocation signature profiles. We evaluated the effects of the AMPK activator AICAR on cell growth, cell cycle regulators and apoptosis of various childhood ALL cells.

Results: We found that treatment with AICAR inhibited cell proliferation, induced cell cycle arrest in G1-phase, and apoptosis in CCRF-CEM (T-ALL), NALM6 (Bp-ALL), REH (Bp-ALL, TEL/AML1) and SupB15 (Bp-ALL, BCR/ABL) cells. These effects were abolished by treatment with the adenosine kinase inhibitor 5'-iodotubericidin prior to addition of AICAR indicating that AICAR's cytotoxicity is mediated through AMPK activation. Moreover, we determined that growth inhibition exerted by AICAR was associated with activation of p38-MAPK and increased expression of the cell cycle regulators p27 and p53. We also demonstrated that AICAR mediated apoptosis through the mitochondrial pathway as revealed by the release of cytochrome C and cleavage of caspase 9. Additionally, AICAR treatment resulted in phosphorylation of Akt suggesting that activation of the PI3K/Akt pathway may represent a compensatory survival mechanism in response to apoptosis and/or cell cycle arrest. Combined treatment with AICAR and the mTOR inhibitor rapamycin resulted in additive anti-proliferative activity ALL cells.

Conclusion: AICAR-mediated AMPK activation was found to be a proficient cytotoxic agent in ALL cells and the mechanism of its anti-proliferative and apoptotic effect appear to be mediated via activation of p38-MAPK pathway, increased expression of cell cycle inhibitory proteins p27 and p53, and downstream effects on the mTOR pathway, hence exhibiting therapeutic potential as a molecular target for the treatment of childhood ALL. Therefore, activation of AMPK by AICAR represents a novel approach to targeted therapy, and suggests a role for AICAR in combination therapy with inhibitors of the PI3K/Akt/mTOR pathways for the treatment of childhood in ALL.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Division / drug effects
  • DNA Replication / drug effects
  • Drug Delivery Systems
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Enzyme Activation / drug effects
  • G1 Phase / drug effects
  • Humans
  • Imidazoles / pharmacology
  • Leukemia-Lymphoma, Adult T-Cell / enzymology
  • Leukemia-Lymphoma, Adult T-Cell / pathology
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / drug effects
  • Neoplasm Proteins / agonists
  • Neoplasm Proteins / antagonists & inhibitors
  • Phosphorylation
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / enzymology
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Prodrugs / pharmacology*
  • Protein Processing, Post-Translational / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridines / pharmacology
  • Ribonucleotides / pharmacology*
  • Sirolimus / pharmacology
  • Tubercidin / analogs & derivatives
  • Tubercidin / pharmacology
  • Tumor Cells, Cultured / drug effects
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Multienzyme Complexes
  • Neoplasm Proteins
  • Prodrugs
  • Pyridines
  • Ribonucleotides
  • 5-iodotubercidin
  • Aminoimidazole Carboxamide
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide
  • Tubercidin
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
  • Sirolimus