title: Decitabine, a DNA methyltransferase inhibitor, induces apoptosis in             human leukemia cells through intracellular reactive oxygen species generation.
abstract: The DNA methyltransferase inhibitor decitabine, 5-aza-2'-deoxycytidine,             has been found to exert anti-metabolic and anticancer activities when tested against             various cultured cancer cells. Furthermore, decitabine has been found to play             critical roles in cell cycle arrest and apoptosis in various cancer cell lines;             however, these roles are not well understood. In this study, we investigated decitabine             for its potential anti-proliferative and apoptotic effects in human leukemia cell             lines U937 and HL60. Our results indicated that treatment with decitabine resulted             in significantly inhibited cell growth in a concentration- and time-dependent             manner by the induction of apoptosis. Decitabine-induced apoptosis in U937 and             HL60 cells was correlated with the downregulation of anti-apoptotic Bcl-2, XIAP,             cIAP-1 and cIAP-2 protein levels, the cleavage of Bid proteins, the activation             of caspases and the collapse of mitochondrial membrane potential (MMP). However,             apoptosis induced by decitabine was attenuated by caspase inhibitors, indicating             an important role for caspases in decitabine responses. The data further demonstrated             that decitabine increased intracellular reactive oxygen species (ROS) generation.             Moreover, N-acetyl-L-cysteine, a widely used ROS scavenger, effectively blocked             the decitabine-induced apoptotic effects via inhibition of ROS production and             MMP collapse. These observations clearly indicate that decitabine-induced ROS             in human leukemia cells are key mediators of MMP collapse, which leads to apoptosis             induction followed by caspase activation.
authors: Department of Molecular Biology, Busan National University, Busan                     609-735, Republic of Korea.
authors: Dong Yeok
authors: DY
authors: Shin
authors: You-Soo
authors: YS
authors: Park
authors: Kwangmo
authors: K
authors: Yang
authors: Gi-Young
authors: GY
authors: Kim
authors: Wun-Jae
authors: WJ
authors: Kim
authors: Min Ho
authors: MH
authors: Han
authors: Ho Sung
authors: HS
authors: Kang
authors: Yung Hyun
authors: YH
authors: Choi
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077209:Decitabine; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis
chemical_list: D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000077209:Decitabine; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D020169:Caspases; D001374:Azacitidine; D000111:Acetylcysteine