Arsenic trioxide induces apoptosis in human platelets via C-Jun NH2-terminal kinase activation.
Arsenic trioxide induces apoptosis in human platelets via C-Jun NH2-terminal kinase activation.
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三氧化二砷通过 C-Jun NH2 末端激酶激活诱导人血小板凋亡
DOI：
10.1371/journal.pone.0086445
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Dai K
中科院分区：
文献类型：
--
作者：
Wu Y;Dai J;Zhang W;Yan R;Zhang Y;Ruan C;Dai K
三氧化二砷（Arsenic trioxide，ATO）是一种古老的中、西药，近年来已成为一种有效的抗肿瘤药物，尤其是在治疗急性早幼粒细胞白血病（acute promyelocytic leukemia，APL）方面有着广泛的应用。然而，ATO治疗的APL或其他恶性疾病患者中大多数发生血小板减少，其发病机制尚不清楚。我们发现ATO剂量依赖性地诱导血小板中线粒体内跨膜电位（Δ Km）的去极化，Bax的上调和Bcl-2和Bcl-XL的下调，caspase-3的激活和磷脂酰丝氨酸（PS）的暴露。ATO不诱导血小板表面P-选择素的表达和PAC-1结合，而明显降低胶原、ADP和凝血酶诱导的血小板聚集。ATO剂量依赖性地诱导c-Jun氨基末端激酶（JNK）激活，JNK特异性抑制剂dicumarol可明显降低ATO诱导的血小板Δ Jun m去极化。将临床治疗剂量的ATO腹腔注射给C57小鼠，连续注射5天后，循环血小板数量明显减少。数据表明ATO通过血小板中的JNK活化诱导半胱天冬酶依赖性细胞凋亡。ATO不引起血小板活化，然而，它不仅损害血小板功能，而且还减少体内循环血小板，提示ATO治疗患者血小板减少症的可能发病机制。
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.
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影响因子：
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作者：
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