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首页> 外文期刊>Cellular Physiology and Biochemistry >Enhanced Erythrocyte Membrane Exposure of Phosphatidylserine Following Sorafenib Treatment: An in vivo and in vitro Study
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Enhanced Erythrocyte Membrane Exposure of Phosphatidylserine Following Sorafenib Treatment: An in vivo and in vitro Study

机译：索拉非尼治疗后增强磷脂酰丝氨酸的红细胞膜暴露：体内和体外研究

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Background: Sorafenib (Nexavar?), a polytyrosine kinase inhibitor, stimulates apoptosis and is thus widely used for chemotherapy in hepatocellular carcinoma (HCC). Hematological side effects of Nexavar? chemotherapy include anemia. Erythrocytes may undergo apoptosis-like suicidal death or eryptosis, which is characterized by cell shrinkage and phosphatidylserine-exposure at the cell surface. Signaling leading to eryptosis include increase in cytosolic Ca~(2+)-activity ([Ca~(2+)]), formation of ceramide, ATP-depletion and oxidative stress. The present study explored, whether sorafenib triggers eryptosis in vitro and in vivo. Methods: [Ca~(2+)]_? was estimated from Fluo3-fluorescence, cell volume from forward scatter, phosphatidylserine-exposurefrom annexin-V-binding, hemolysis from hemoglobin release, ceramide with antibody binding-dependent fluorescence, cytosolic ATP with a luciferin-luciferase-based assay, and oxidative stress from 2',7' dichlorodihydrofluorescein diacetate (DCFDA) fluorescence. Results: A 48 h exposure of erythrocytes to sorafenib (>0.5|jM) significantly increased Fluo 3 fluorescence, decreased forward scatter, increased annexin-V-binding and triggered slight hemolysis (>5μM), but did not significantly modify ceramide abundance and cytosolic ATP. Sorafenib treatment significantly enhanced DCFDA-fluorescence and the reducing agents N-acetyl-L-cysteine and tiron significantly blunted sorafenib-induced phosphatidylserine exposure. Nexavar? chemotherapy in HCC patients significantly enhanced the number of phosphatidylserine-exposing erythrocytes. Conclusions: The present observations disclose novel effects of sorafenib, i.e. stimulation of suicidal erythrocyte death or eryptosis, which may contribute to the pathogenesis of anemia in Nexavar?-based chemotherapy.
机译：背景：索拉非尼（Nexavar？）是一种多酪氨酸激酶抑制剂，可刺激细胞凋亡，因此被广泛用于肝细胞癌（HCC）的化疗。 Nexavar的血液学副作用？化疗包括贫血。红细胞可能会发生类似凋亡的自杀性死亡或隐匿性死亡，其特征是细胞萎缩和细胞表面磷脂酰丝氨酸暴露。导致加密的信​​号包括细胞质Ca〜（2 +）-活性（[Ca〜（2+）]）的增加，神经酰胺的形成，ATP的消耗和氧化应激。本研究探讨了索拉非尼是否在体内和体外触发加密作用。方法：[Ca〜（2 +）] _？通过Fluo3-荧光，前向散射的细胞体积，膜联蛋白-V结合的磷脂酰丝氨酸暴露，血红蛋白释放的溶血，具有抗体结合依赖性荧光的神经酰胺，基于萤光素-萤光素酶的测定的胞浆ATP以及氧化应激进行了估计2'，7'二氯二氢荧光素二乙酸酯（DCFDA）荧光。结果：红细胞暴露于索拉非尼（> 0.5 | jM）48小时会显着增加Fluo 3荧光，减少前向散射，增加膜联蛋白-V结合并触发轻微溶血（>5μM），但不会显着改变神经酰胺的丰度和胞质ATP。索拉非尼治疗显着增强DCFDA荧光，还原剂N-乙酰基-L-半胱氨酸和铁离子显着减弱索拉非尼诱导的磷脂酰丝氨酸暴露。 Nexavar？ HCC患者的化疗显着增加了暴露于磷脂酰丝氨酸的红细胞数量。结论：目前的观察结果揭示了索拉非尼的新作用，即刺激自杀性红细胞死亡或隐匿性刺激，这可能有助于基于Nexavar？的化疗中贫血的发病机理。

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