title: cAMP protects acute promyelocytic leukemia cells from arsenic trioxide-induced caspase-3 activation and apoptosis.
abstract: More recently, arsenic trioxide (ATO), was integrated into acute promyelocytic leukemia (APL) treatment, showing high efficacy and tolerability in patients with both ATRA-sensitive and ATRA-resistant APL. ATO could induce apoptosis at relatively high concentrations (0.5 to 2.0 micromol/L) and partial differentiation at low concentrations (0.1 to 0.5 micromol/L) in leukemic promyelocytes. It is known that cAMP agonists enhance low-dose ATO-induced APL cells differentiation. Less well appreciated was the possible interaction between relatively high-doses of ATO and enhanced levels of cAMP in APL cells. Here, we show that elevation of cAMP levels by forskolin inhibited ATO-mediated apoptosis in APL-derived NB4 cells, and this inhibition could be averted by cell permeable cAMP-dependent protein kinase inhibitor (14-22) amide. Inactivating phosphorylation of the proapoptotic protein Bad at Ser118 and phosphorylation of the CREB proto-oncogene at Ser133 were observed upon elevation of cAMP levels in NB4 cells. Phosphorylation of these PKA target proteins is known to promote cell survival in AML cells. The ability of cAMP to endow the APL cells with survival advantage is of particular importance when cAMP agonists may be considered as adjuncts to APL therapy.
authors.affiliation: Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address: safa.m@iums.ac.ir.
authors.forename: Majid
authors.initials: M
authors.lastname: Safa
authors.affiliation: Oncopathology Research Center, and Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address: mousavik@gmail.com.
authors.forename: Kazem
authors.initials: K
authors.lastname: Mousavizadeh
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Shekoofeh
authors.initials: S
authors.lastname: Noori
authors.affiliation: Department of Medical Laboratory Sciences, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Arefeh
authors.initials: A
authors.lastname: Pourfathollah
authors.affiliation: National Institute and Faculty of Nutrition and Food Technology, Department of Molecular Nutrition, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Hamid
authors.initials: H
authors.lastname: Zand
mesh_terms: D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D010087:Oxides; D000090063:Proto-Oncogene Mas; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C494819:BAD protein, human; C000715470:MAS1 protein, human; D010087:Oxides; D000090063:Proto-Oncogene Mas; D016159:Tumor Suppressor Protein p53; D051025:bcl-Associated Death Protein; D005576:Colforsin; D004247:DNA; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D053148:Caspase 3; D000077237:Arsenic Trioxide
keywords: Apoptosis; Arsenic trioxide; NB4 cells; cAMP