title: Cyclic AMP efflux inhibitors as potential therapeutic agents for leukemia.
abstract: Apoptotic evasion is a hallmark of cancer. We propose that some cancers may evade cell death by regulating 3'-5'-cyclic adenosine monophosphate (cAMP), which is associated with pro-apoptotic signaling. We hypothesize that leukemic cells possess mechanisms that efflux cAMP from the cytoplasm, thus protecting them from apoptosis. Accordingly, cAMP efflux inhibition should result in: cAMP accumulation, activation of cAMP-dependent downstream signaling, viability loss, and apoptosis. We developed a novel assay to assess cAMP efflux and performed screens to identify inhibitors. In an acute myeloid leukemia (AML) model, several identified compounds reduced cAMP efflux, appropriately modulated pathways that are responsive to cAMP elevation (cAMP-responsive element-binding protein phosphorylation, and deactivation of Very Late Antigen-4 integrin), and induced mitochondrial depolarization and caspase activation. Blocking adenylyl cyclase activity was sufficient to reduce effects of the most potent compounds. These compounds also decreased cAMP efflux and viability of B-lineage acute lymphoblastic leukemia (B-ALL) cell lines and primary patient samples, but not of normal primary peripheral blood mononuclear cells. Our data suggest that cAMP efflux is a functional feature that could be therapeutically targeted in leukemia. Furthermore, because some of the identified drugs are currently used for treating other illnesses, this work creates an opportunity for repurposing.
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.|University of New Mexico Center for Molecular Discovery, Albuquerque, NM, USA.|Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Dominique R
authors.initials: DR
authors.lastname: Perez
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.|University of New Mexico Center for Molecular Discovery, Albuquerque, NM, USA.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Smagley
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.|University of New Mexico Center for Molecular Discovery, Albuquerque, NM, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Garcia
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.|University of New Mexico Center for Molecular Discovery, Albuquerque, NM, USA.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Carter
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.|University of New Mexico Center for Molecular Discovery, Albuquerque, NM, USA.|Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Evangelisti
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.|Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Matlawska-Wasowska
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.|Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Winter
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.|University of New Mexico Center for Molecular Discovery, Albuquerque, NM, USA.|Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.|University of New Mexico Center for Molecular Discovery, Albuquerque, NM, USA.|Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chigaev
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods; D058492:Drug Repositioning; D057166:High-Throughput Screening Assays; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015290:Second Messenger Systems / Q000187:drug effects; D014407:Tumor Cells, Cultured; D020298:U937 Cells
chemical_list: D000262:Adenylyl Cyclases; D000970:Antineoplastic Agents; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D039041:Integrin alpha4beta1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C073492:ABCC4 protein, human; C115163:CREB1 protein, human
keywords: cyclic AMP; drug repurposing; efflux; evasion of apoptosis; leukemia