Graduate Institute of Medical Sciences, Department of Pharmacology, Taipei Medical University, Taipei, Taiwan.
Transl Res. 2010 Feb;155(2):97-108. doi: 10.1016/j.trsl.2009.08.005. Epub 2009 Sep 15.
Arsenic trioxide produces high rates of complete clinical remission in patients with relapsed/refractory acute promyelocytic leukemia. Platelet activation is relevant in a variety of acute thrombotic events and coronary heart diseases. Few studies have examined the effects of arsenic trioxide on platelets, and the mechanisms underlying the signaling pathways remain obscure. The aim of this study was to examine systematically the detailed mechanisms of arsenic trioxide in preventing platelet activation. Arsenic trioxide (5 micromol/L) exhibited more potent activity at inhibiting collagen (1 microg/mL)-induced platelet aggregation than other agonists. Arsenic trioxide (15 and 25 micromol/L) inhibited collagen-induced platelet activation accompanied by [Ca(+2)]i mobilization, thromboxane A(2) (TxA(2)) formation, phospholipase C (PLC)gamma 2 phosphorylation, and protein kinase C (PKC) activation. Arsenic trioxide (15 and 25 micromol/L) did not significantly affect cyclic nucleotide-induced vasodilator-stimulated phosphoprotein phosphorylation. Moreover, arsenic trioxide markedly inhibited p38 mitogen-activated protein kinase (MAPK) but not JNK1/2 or ERK2 phosphorylation in washed platelets. Arsenic trioxide also markedly reduced hydroxyl radical (OH(.)) formation in the erythrocyte sedimentation rate (ESR) study. The most important findings of this study suggest that the inhibitory effect of arsenic trioxide possibly involves inhibition of the PLC gamma 2-PKC-p38 MAPK cascade, thereby leading to inhibition of [Ca(+2)]i or free radical formation, and finally the inhibition of platelet aggregation.
三氧化二砷可使复发/难治性急性早幼粒细胞白血病患者获得很高的完全临床缓解率。血小板激活与多种急性血栓事件和冠心病有关。很少有研究探讨三氧化二砷对血小板的影响，其信号通路的机制仍不清楚。本研究旨在系统地研究三氧化二砷在防止血小板激活方面的详细机制。三氧化二砷（5 微摩尔/升）在抑制胶原（1 微克/毫升）诱导的血小板聚集方面比其他激动剂具有更强的活性。三氧化二砷（15 和 25 微摩尔/升）抑制胶原诱导的血小板激活，同时伴有[Ca(+2)]i 动员、血栓烷 A(2)（TxA(2))形成、磷脂酶 C (PLC)γ2 磷酸化和蛋白激酶 C (PKC)激活。三氧化二砷（15 和 25 微摩尔/升）对环核苷酸诱导的血管舒张刺激磷蛋白磷酸化没有显著影响。此外，三氧化二砷明显抑制了洗涤血小板中的 p38 丝裂原活化蛋白激酶（MAPK），但不抑制 JNK1/2 或 ERK2 磷酸化。三氧化二砷在红细胞沉降率（ESR）研究中也明显减少了羟基自由基（OH(.))的形成。本研究的最重要发现表明，三氧化二砷的抑制作用可能涉及抑制 PLCγ2-PKC-p38 MAPK 级联反应，从而导致[Ca(+2)]i 或自由基形成的抑制，最终抑制血小板聚集。
