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

Shuping Wang,Zhilin Wang,Zhirong Geng,Min Zhou,Jian Ouyang,Ying-Jan Wang

doi:10.1371/journal.pone.0130343

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.

Highlights

Acute promyelocytic leukemia (APL) is an M3 subtype of acute myeloid leukemia [1]
The typical characteristic of APL is the specific chromosomal translocation t(15;17) (q22;q21), which induces the expression of the promyelocytic leukemia-retinoic acid receptor α (PML-RARα) oncoprotein [1,2,3]
The viability of NB4 and primary APL cells was determined by trypan blue exclusion [28]

Summary

Introduction

Acute promyelocytic leukemia (APL) is an M3 subtype of acute myeloid leukemia [1]. The typical characteristic of APL is the specific chromosomal translocation t(15;17) (q22;q21), which induces the expression of the promyelocytic leukemia-retinoic acid receptor α (PML-RARα) oncoprotein [1,2,3]. All-trans retinoic acid and arsenic trioxide (As3+), have hitherto been successfully used in the treatment of APL [4,5,6]. At high concentrations (0.5–2.0 μM), As3+ triggers apoptosis, and at low concentrations (0.1–0.5μM) it induces partial differentiation. Mechanism of Combining As4S4 and As3+ in APL Treatment study design, data collection and analysis, decision to publish, or preparation of the manuscript

Methods

Results

Discussion

Conclusion