title: Bcl-2high mantle cell lymphoma cells are sensitized to acadesine with ABT-199.
abstract: Acadesine is a nucleoside analogue with known activity against B-cell malignancies. Herein, we showed that in mantle cell lymphoma (MCL) cells acadesine induced caspase-dependent apoptosis through turning on the mitochondrial apoptotic machinery. At the molecular level, the compound triggered the activation of the AMPK pathway, consequently modulating known downstream targets, such as mTOR and the cell motility-related vasodilator-stimulated phosphoprotein (VASP). VASP phosphorylation by acadesine was concomitant with a blockade of CXCL12-induced migration. The inhibition of the mTOR cascade by acadesine, committed MCL cells to enter in apoptosis by a translational downregulation of the antiapoptotic Mcl-1 protein. In contrast, Bcl-2 protein levels were unaffected by acadesine and MCL samples expressing high levels of Bcl-2 tended to have a reduced response to the drug. Targeting Bcl-2 with the selective BH3-mimetic agent ABT-199 sensitized Bcl-2high MCL cells to acadesine. This effect was validated in vivo, where the combination of both agents displayed a more marked inhibition of tumor outgrowth than each drug alone. These findings support the notions that antiapoptotic proteins of the Bcl-2 family regulate MCL cell sensitivity to acadesine and that the combination of this agent with Bcl-2 inhibitors might be an interesting therapeutic option to treat MCL patients.
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Montraveta
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Xargay-Torrent
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Rosich
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Unitat d'Hematopatologia, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: López-Guerra
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Jocabed
authors.initials: J
authors.lastname: Roldán
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Vanina
authors.initials: V
authors.lastname: Rodríguez
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Eriong
authors.initials: E
authors.lastname: Lee-Vergés
authors.affiliation: Advancell-Advanced In Vitro Cell Technologies S.A., Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: de Frías
authors.affiliation: Advancell-Advanced In Vitro Cell Technologies S.A., Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Campàs
authors.affiliation: Unitat d'Hematopatologia, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Gaël
authors.initials: G
authors.lastname: Roué
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Unitat d'Hematopatologia, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
mesh_terms: D000199:Actins / Q000737:chemistry; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D017209:Apoptosis; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012263:Ribonucleosides / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000199:Actins; C000595707:BCL2 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; C515255:CXCL12 protein, human; D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; C579095:MCL1 protein, human; D008840:Microfilament Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012263:Ribonucleosides; D013449:Sulfonamides; D000098662:Vasodilator-Stimulated Phosphoprotein; D000620:Aminoimidazole Carboxamide; C011651:acadesine; C579720:venetoclax
keywords: ABT-199; Bcl-2; Mcl-1; acadesine (AICAR); mantle cell lymphoma