title: Decitabine and SAHA-induced apoptosis is accompanied by survivin downregulation and potentiated by ATRA in p53-deficient cells.
abstract: While p53-dependent apoptosis is triggered by combination of methyltransferase inhibitor decitabine (DAC) and histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in leukemic cell line CML-T1, reactive oxygen species (ROS) generation as well as survivin and Bcl-2 deregulation participated in DAC + SAHA-induced apoptosis in p53-deficient HL-60 cell line. Moreover, decrease of survivin expression level is accompanied by its delocalization from centromere-related position in mitotic cells suggesting that both antiapoptotic and cell cycle regulation roles of survivin are affected by DAC + SAHA action. Addition of subtoxic concentration of all-trans-retinoic acid (ATRA) increases the efficiency of DAC + SAHA combination on viability, apoptosis induction, and ROS generation in HL-60 cells but has no effect in CML-T1 cell line. Peripheral blood lymphocytes from healthy donors showed no damage induced by DAC + SAHA + ATRA combination. Therefore, combination of ATRA with DAC and SAHA represents promising tool for therapy of leukemic disease with nonfunctional p53 signalization.
authors.affiliation: Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague 2, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Brodská
authors.affiliation: Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague 2, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Otevřelová
authors.affiliation: Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague 2, Czech Republic.
authors.forename: Aleš
authors.initials: A
authors.lastname: Holoubek
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000633:toxicity; D045744:Cell Line, Tumor; D000077209:Decitabine; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077022:Survivin; D014212:Tretinoin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*; D000077337:Vorinostat
chemical_list: D000964:Antimetabolites, Antineoplastic; C107489:BIRC5 protein, human; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D017382:Reactive Oxygen Species; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D014212:Tretinoin; D000077337:Vorinostat; D000077209:Decitabine; D001374:Azacitidine