title: Docetaxel Facilitates Endothelial Dysfunction through Oxidative Stress via Modulation of Protein Kinase C Beta: The Protective Effects of Sotrastaurin.
abstract: 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.
authors: *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.
authors: Ching-Hsia
authors: CH
authors: Hung
authors: *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.
authors: Shih-Hung
authors: SH
authors: Chan
authors: *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.
authors: Pei-Ming
authors: PM
authors: Chu
authors: *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 kunlingtsai@mail.ncku.edu.tw.
authors: Kun-Ling
authors: KL
authors: Tsai
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D000077143:Docetaxel; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000503:physiopathology*; D005978:Glutathione / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018384:Oxidative Stress; D064546:Protein Kinase C beta / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043823:Taxoids / Q000633:toxicity*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011758:Pyrroles; D011799:Quinazolines; D017382:Reactive Oxygen Species; D043823:Taxoids; D000077143:Docetaxel; C543528:sotrastaurin; D064546:Protein Kinase C beta; D005978:Glutathione
keywords: NADPH oxidase; docetaxel; protein kinase C; sotrastaurin
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