title: Tetraarsenictetrasulfide and Arsenic Trioxide Exert Synergistic Effects on Induction of Apoptosis and Differentiation in Acute Promyelocytic Leukemia Cells.
abstract: Since arsenic trioxide (As3+) has been successfully used in the treatment of acute promyelocytic leukemia (APL), its adverse effects on patients have been problematic and required a solution. Considering the good therapeutic potency and low toxicity of tetraarsenictetrasulfide (As4S4) in the treatment of APL, we investigated the effects of combining As4S4 and As3+ on the apoptosis and differentiation of NB4 and primary APL cells. As4S4, acting similarly to As3+, arrested the G1/S transition, induced the accumulation of cellular reactive oxygen species, and promoted apoptosis. Additionally, low concentrations of As4S4 (0.1-0.4 μM) induced differentiation of NB4 and primary APL cells. Compared with the As4S4- or As3+-treated groups, the combination of As4S4 and As3+ obviously promoted apoptosis and differentiation of NB4 and primary APL cells. Mechanistic studies suggested that As4S4 acted synergistically with As3+ to down-regulate Bcl-2 and nuclear factor-κB expression, up-regulate Bax and p53 expression, and induce activation of caspase-12 and caspase-3. Moreover, the combination of low concentrations of As4S4 and As3+ enhanced degradation of the promyelocytic leukemia-retinoic acid receptor α oncoprotein. In summary, As4S4 and As3+ synergistically induce the apoptosis and differentiation of NB4 and primary APL cells.
authors.affiliation: State key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210093, China.
authors.forename: Shuping
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Hematology, DrumTower Hospital of Medical School, Nanjing University, Nanjing, 210093, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Hematology, DrumTower Hospital of Medical School, Nanjing University, Nanjing, 210093, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: State key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210093, China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Geng
authors.affiliation: State key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210093, China.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage*; D002454:Cell Differentiation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010087:Oxides / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013440:Sulfides / Q000008:administration & dosage*
chemical_list: D001152:Arsenicals; D009363:Neoplasm Proteins; D010087:Oxides; D017382:Reactive Oxygen Species; D013440:Sulfides; D000077237:Arsenic Trioxide; C534735:tetraarsenic tetrasulfide