Cyclic AMP efflux inhibitors as potential therapeutic agents for leukemia
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Dominique R. Perez1,2,3, Yelena Smagley1,2, Matthew Garcia1,2, Mark B. Carter1,2, Annette Evangelisti1,2,3, Ksenia Matlawska-Wasowska1,4, Stuart S. Winter1,4, Larry A. Sklar1,2,3 and Alexandre Chigaev1,2,3
1 University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA
2 University of New Mexico Center for Molecular Discovery, Albuquerque, NM, USA
3 Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
4 Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
Alexandre Chigaev, email:
Keywords: cyclic AMP, drug repurposing, efflux, evasion of apoptosis, leukemia
Received: April 14, 2016 Accepted: April 16, 2016 Published: April 25, 2016
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.
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