| AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells. | |
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MedLine Citation:
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PMID: 20664053 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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5-Aminoimidazole-4-carboxamide riboside or acadesine (AICAR) induces apoptosis in chronic lymphocytic leukemia (CLL) cells. A clinical study of AICAR is currently being performed in patients with this disease. Here, we have analyzed the mechanisms involved in AICAR-induced apoptosis in CLL cells in which it activates its only well-known molecular target, adenosine monophosphate-activated protein kinase (AMPK). However, AMPK activation with phenformin or A-769662 failed to induce apoptosis in CLL cells and AICAR also potently induced apoptosis in B lymphocytes from Ampkα1(-/-) mice, demonstrating an AMPK-independent mechanism of cell death. Importantly, AICAR induced apoptosis irrespective of the tumor suppressor TP53 or ataxia telangiectasia mutated (ATM) status via induction of the mitochondrial pathway. Apoptosis was preceded by an increase in mRNA and protein levels of proapoptotic BCL-2 family proteins of the BH3-only subgroup, including BIM, NOXA, and PUMA in CLL cells. Strikingly, B lymphocytes from Noxa(-/-) or Bim(-/-) mice were partially protected from the cytotoxic effects of AICAR. Consistently, B cells from Noxa(-/-)/Bim(-/-) mice resisted induction of apoptosis by AICAR as potently as B lymphocytes overexpressing transgenic BCL-2. These findings support the notion that AICAR is an interesting alternative therapeutic option for CLL patients with impaired p53 function and resistance to conventional chemotherapy. |
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Authors:
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Antonio F Santidrián; Diana M González-Gironès; Daniel Iglesias-Serret; Llorenç Coll-Mulet; Ana M Cosialls; Mercè de Frias; Clara Campàs; Eva González-Barca; Esther Alonso; Verena Labi; Benoit Viollet; Adalberto Benito; Gabriel Pons; Andreas Villunger; Joan Gil |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-27 |
Journal Detail:
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Title: Blood Volume: 116 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-22 Completed Date: 2010-11-29 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 3023-32 Citation Subset: AIM; IM |
Affiliation:
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Departament de Ciències Fisiològiques II, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)-Universitat de Barcelona, L'Hospitalet de Llobregat, Spain. |
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| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases
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metabolism* Adult Aged Aged, 80 and over Aminoimidazole Carboxamide / analogs & derivatives*, pharmacology Animals Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Apoptosis Regulatory Proteins / genetics* Cell Line, Tumor Cells, Cultured Female Gene Expression Regulation, Leukemic / drug effects Humans Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*, genetics, metabolism Male Membrane Proteins / genetics* Mice Middle Aged Proto-Oncogene Proteins / genetics* Proto-Oncogene Proteins c-bcl-2 / genetics* Ribonucleosides / pharmacology* Tumor Suppressor Protein p53 / metabolism* Up-Regulation / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Apoptosis Regulatory Proteins; 0/Bcl-2-like protein 11; 0/Membrane Proteins; 0/PMAIP1 protein, human; 0/Pmaip1 protein, mouse; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Ribonucleosides; 0/Tumor Suppressor Protein p53; 2627-69-2/acadesine; 360-97-4/Aminoimidazole Carboxamide; EC 2.7.11.1/AMP-Activated Protein Kinases |
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