title: Decitabine-induced apoptosis is derived by Puma and Noxa induction in chronic myeloid leukemia cell line as well as in PBL and is potentiated by SAHA.
abstract: Restoration of cellular apoptotic pathways plays a crucial role in cancer therapy strategies. In a broad spectrum of anticancer drugs, epigenetic effectors are in the center of interest mostly because of potential reversibility of their action. Methylation status of the cells is influenced by methyltransferase inhibitor 2-deoxy-5'-azacytidine (decitabine, DAC), but higher concentrations of this agent cause a DNA-damage. In our study, tumor supressor p53-apoptotic pathway was activated in decitabine-induced cell death. Expression of p53-inducible BH3-only apoptotic proteins Puma and Noxa was elevated and large activation of executive caspases was observed. The extent of acetylation in the cell is affected by histonedeacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Combination of SAHA with decitabine brought synergistic effect on apoptosis triggering in CML-T1 cell line, but apoptosis as well as necrosis occurred also in normal peripheral blood lymphocytes. Therefore, promising potential of such combined therapy calls for more detailed investigation of unwanted effects in normal cells.
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic. brodska@uhkt.cz
authors.forename: Barbora
authors.initials: B
authors.lastname: Brodská
authors.forename: Petra
authors.initials: P
authors.lastname: Otevřelová
authors.forename: Aleš
authors.initials: A
authors.lastname: Holoubek
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D000077209:Decitabine; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000077337:Vorinostat
chemical_list: D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D006877:Hydroxamic Acids; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077337:Vorinostat; D000077209:Decitabine; D001374:Azacitidine