Tetraarsenictetrasulfide and Arsenic Trioxide Exert Synergistic Effects on Induction of Apoptosis and Differentiation in Acute Promyelocytic Leukemia Cells

PLoS One. 2015 Jun 25;10(6):e0130343. doi: 10.1371/journal.pone.0130343. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Arsenic Trioxide
  • Arsenicals / administration & dosage*
  • Cell Differentiation / drug effects
  • Drug Resistance, Neoplasm
  • Drug Synergism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Leukemia, Promyelocytic, Acute / drug therapy*
  • Leukemia, Promyelocytic, Acute / genetics
  • Leukemia, Promyelocytic, Acute / pathology
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Oxides / administration & dosage*
  • Reactive Oxygen Species / metabolism
  • Sulfides / administration & dosage*

Substances

  • Arsenicals
  • Neoplasm Proteins
  • Oxides
  • Reactive Oxygen Species
  • Sulfides
  • Arsenic Trioxide
  • tetraarsenic tetrasulfide

Grants and funding

ZW was supported by the National Basic Research Program of China (2013CB922102), (http://www.973.gov.cn/English/Index.aspx) and the National Natural Science Foundation of China (21275072 and 21475059) (www.nsfc.gov.cn). ZG was supported by the National Natural Science Foundation of China (21201101) (www.nsfc.gov.cn). SW was supported by the Scientific Research Innovation Project for Postgraduates of Jiansu Province (CXZZ12-0038) (http://www.ec.js.edu.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.