Laboratoire de Recherche en Inflammation et Physiologie des Granulocytes, Université du Québec, INRS-Institut Armand-Frappier, Laval, QC, Canada.
Toxicol In Vitro. 2010 Apr;24(3):936-41. doi: 10.1016/j.tiv.2009.11.011. Epub 2009 Nov 16.
The anticancer dug arsenic trioxide (ATO) is known to be toxic for human mononuclear and neutrophil cell populations by a mechanism that needs to be further investigated. Due to the well-characterized role of Syk kinase in phagocytosis and because activation and involvement of Syk in response to ATO treatment has never been reported in any cells, we decided to determine whether or not Syk is involved in the mode of action of ATO. Human neutrophils were freshly isolated and incubated in vitro with ATO and the role of Syk was evaluated in different neutrophil functions. We found that ATO increased phosphorylation of Syk and this was reversed by piceatannol, a Syk-specific pharmacological inhibitor. In addition, ATO increased the phagocytic ability of neutrophils and degranulation via Syk activation. Finally, using both pharmacological inhibition and cellular depletion of Syk via an antisense approach, we found that this kinase is involved in apoptosis. We conclude that Syk activation is an important step in the mode of action of ATO in mature immune cells such as neutrophils and is involved in rapid, intermediate and lengthy biological processes. This is the first study to report that Syk is activated by ATO.
砷三氧化物（ATO）具有抗癌作用，但它会对人单核细胞和中性粒细胞产生毒性，其具体机制尚待进一步研究。由于 Src 相关酪氨酸激酶（Syk）在吞噬作用中的作用已得到充分证实，而且 Src 激酶在对 ATO 治疗的反应中的激活和参与从未在任何细胞中报道过，因此我们决定确定 Syk 是否参与 ATO 的作用机制。我们将新鲜分离的人中性粒细胞在体外与 ATO 孵育，并评估 Syk 在不同中性粒细胞功能中的作用。我们发现 ATO 增加了 Syk 的磷酸化，而 Syk 的特异性药理学抑制剂白藜芦醇可逆转这一作用。此外，ATO 通过 Syk 激活增加了中性粒细胞的吞噬能力和脱颗粒作用。最后，我们通过药理学抑制和细胞耗竭两种方法（分别使用 Syk 的药理学抑制剂和反义寡核苷酸）发现，该激酶参与了细胞凋亡。我们的结论是，Syk 的激活是 ATO 在成熟免疫细胞（如中性粒细胞）中作用机制的重要步骤，涉及快速、中期和长期的生物学过程。这是第一项报道 ATO 激活 Syk 的研究。
