Hung Ching-Hsia, Chan Shih-Hung, Chu Pei-Ming, Tsai Kun-Ling
*Department of Physical Therapy, National Cheng Kung University, Tainan, Taiwan, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan and Department of Anatomy, School of Medicine, China Medical University, Taichung, Taiwan.
*Department of Physical Therapy, National Cheng Kung University, Tainan, Taiwan, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan and Department of Anatomy, School of Medicine, China Medical University, Taichung, Taiwan
Toxicol Sci. 2015 May;145(1):59-67. doi: 10.1093/toxsci/kfv017. Epub 2015 Jan 28.
Docetaxel (DTX), a taxane drug, has widely been used as an anticancer or antiangiogenesis drug. However, DTX caused side effects, such as vessel damage and phlebitis, which may reduce its clinical therapeutic efficacy. The molecular mechanisms of DTX that cause endothelial dysfunction remain unclear. The aim of this study as to validate the probable mechanisms of DTX-induced endothelial dysfunction in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were stimulated with DTX (2.5, 5, and 10nM) for 24 h to induce endothelial dysfunction. Stimulation with DTX reduced cell viability in a concentration- and time-dependent manner. DTX upregulated caspase-3 activity and TUNEL-positive cells. DTX treatment also increased PKCβ phosphorylation levels and NADPH oxidase activity, which resulted in ROS formation. However, all of these findings were reversed by PKCβ inhibition and NADPH oxidase repression. Finally, we demonstrated that sotrastaurin (AEB-071), a new PKCβ inhibitor, mitigated DTX-induced oxidative injury in endothelial cells. Our findings from this study provide a probable molecular mechanism of DTX-induced oxidative injury in endothelial cells and a new clinical and therapeutic approach for preventing DTX-mediated vessel injury.
多西他赛（DTX）是一种紫杉烷类药物，已被广泛用作抗癌或抗血管生成药物。然而，DTX会引起诸如血管损伤和静脉炎等副作用，这可能会降低其临床治疗效果。DTX导致内皮功能障碍的分子机制仍不清楚。本研究的目的是验证DTX诱导内皮细胞内皮功能障碍的可能机制。用DTX（2.5、5和10nM）刺激人脐静脉内皮细胞（HUVECs）24小时以诱导内皮功能障碍。DTX刺激以浓度和时间依赖性方式降低细胞活力。DTX上调了caspase-3活性和TUNEL阳性细胞。DTX处理还增加了PKCβ磷酸化水平和NADPH氧化酶活性，导致活性氧形成。然而，PKCβ抑制和NADPH氧化酶抑制可逆转所有这些发现。最后，我们证明了一种新的PKCβ抑制剂索拉苏林（AEB-071）减轻了DTX诱导的内皮细胞氧化损伤。我们这项研究的结果提供了DTX诱导内皮细胞氧化损伤的可能分子机制以及预防DTX介导的血管损伤的新临床和治疗方法。
