Arsenic Trioxide Induces Apoptosis in Human Platelets via C-Jun NH2-Terminal Kinase Activation

Yicun Wu,Jin Dai,Kesheng Dai,Changgeng Ruan,Weilin Zhang,Rong Yan,Yiwen Zhang,Ching-Ping Tseng

doi:10.1371/journal.pone.0086445

Abstract

Arsenic trioxide (ATO), one of the oldest drugs in both Western and traditional Chinese medicine, has become an effective anticancer drug, especially in the treatment of acute promyelocytic leukemia (APL). However, thrombocytopenia occurred in most of ATO-treated patients with APL or other malignant diseases, and the pathogenesis remains unclear. Here we show that ATO dose-dependently induces depolarization of mitochondrial inner transmembrane potential (ΔΨm), up-regulation of Bax and down-regulation of Bcl-2 and Bcl-XL, caspase-3 activation, and phosphotidylserine (PS) exposure in platelets. ATO did not induce surface expression of P-selectin and PAC-1 binding, whereas, obviously reduced collagen, ADP, and thrombin induced platelet aggregation. ATO dose-dependently induced c-Jun NH2-terminal kinase (JNK) activation, and JNK specific inhibitor dicumarol obviously reduced ATO-induced ΔΨm depolarization in platelets. Clinical therapeutic dosage of ATO was intraperitoneally injected into C57 mice, and the numbers of circulating platelets were significantly reduced after five days of continuous injection. The data demonstrate that ATO induces caspase-dependent apoptosis via JNK activation in platelets. ATO does not incur platelet activation, whereas, it not only impairs platelet function but also reduces circulating platelets in vivo, suggesting the possible pathogenesis of thrombocytopenia in patients treated with ATO.

Highlights

Arsenic trioxide (ATO), one of the oldest drugs in both Western and traditional Chinese medicine, has become one of the most effective anticancer drugs, especially in the treatment of acute promyelocytic leukemia (APL) [1]
In order to investigate whether ATO induces platelet apoptosis, platelets were incubated with different concentrations of ATO, and platelet DYm depolarization was tested by flow cytometry
It has generally accepted that ATO exerts its anticancer effect by inducing different kinds of malignant cells apoptosis [11,12,13,14,15], it still remains unclear whether ATO incurs platelet apoptosis

Summary

Introduction

Arsenic trioxide (ATO), one of the oldest drugs in both Western and traditional Chinese medicine, has become one of the most effective anticancer drugs, especially in the treatment of acute promyelocytic leukemia (APL) [1]. ATO appears to be the most effective single agent in the treatment of APL and there have been very few reports of primary resistance [2]. ATO has been approved by the Federal Drug Administration for treating all-trans retinoic acid (ATRA)-resistant APL [3]. ATO has appeared to be one of the most promising general anticancer drugs for many kinds of malignance, such as lymphoma [4], hepatocellular carcinoma [5], myelodysplastic syndrome [6]. Studies by different groups indicate that thrombocytopenia is a frequent hematological side effect during the treatment of ATO in patients with myelodysplastic syndrome [6], multiple myeloma [11], metastatic melanoma [12], and hepatocellular carcinoma [13].

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Conclusion