title: AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells.
abstract: 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.
authors.affiliation: Departament de Ciències Fisiològiques II, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)-Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Santidrián
authors.forename: Diana M
authors.initials: DM
authors.lastname: González-Gironès
authors.forename: Daniel
authors.initials: D
authors.lastname: Iglesias-Serret
authors.forename: Llorenç
authors.initials: L
authors.lastname: Coll-Mulet
authors.forename: Ana M
authors.initials: AM
authors.lastname: Cosialls
authors.forename: Mercè
authors.initials: M
authors.lastname: de Frias
authors.forename: Clara
authors.initials: C
authors.lastname: Campàs
authors.forename: Eva
authors.initials: E
authors.lastname: González-Barca
authors.forename: Esther
authors.initials: E
authors.lastname: Alonso
authors.forename: Verena
authors.initials: V
authors.lastname: Labi
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Adalberto
authors.initials: A
authors.lastname: Benito
authors.forename: Gabriel
authors.initials: G
authors.lastname: Pons
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Joan
authors.initials: J
authors.lastname: Gil
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D012263:Ribonucleosides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; C498702:PMAIP1 protein, human; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012263:Ribonucleosides; D016159:Tumor Suppressor Protein p53; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D055372:AMP-Activated Protein Kinases