Cyclic AMP efflux inhibitors as potential therapeutic agents for leukemia.

Academic Article

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.
  • Published In

  • Oncotarget  Journal
  • Keywords

  • cyclic AMP, drug repurposing, efflux, evasion of apoptosis, leukemia, Adenylyl Cyclases, Antineoplastic Agents, Apoptosis, Cell Survival, Cyclic AMP, Cyclic AMP Response Element-Binding Protein, Dose-Response Relationship, Drug, Drug Discovery, Drug Repositioning, High-Throughput Screening Assays, Humans, Integrin alpha4beta1, Membrane Potential, Mitochondrial, Multidrug Resistance-Associated Proteins, Phosphorylation, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Second Messenger Systems, Tumor Cells, Cultured, U937 Cells
  • Digital Object Identifier (doi)

    Author List

  • Perez DR; Smagley Y; Garcia M; Carter MB; Evangelisti A; Matlawska-Wasowska K; Winter SS; Sklar LA; Chigaev A
  • Start Page

  • 33960
  • End Page

  • 33982
  • Volume

  • 7
  • Issue

  • 23