Journal
TOXICOLOGICAL SCIENCES
Volume 145, Issue 1, Pages 59-67Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfv017
Keywords
docetaxel; protein kinase C; NADPH oxidase; sotrastaurin
Categories
Funding
- Ministry of Science and Technology [NSC 100-2314-B-039-017-MY3, MOST 103-2320-B-006-050]
- National Cheng Kung University [D103-35A13]
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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 PKC beta phosphorylation levels and NADPH oxidase activity, which resulted in ROS formation. However, all of these findings were reversed by PKC beta inhibition and NADPH oxidase repression. Finally, we demonstrated that sotrastaurin (AEB-071), a new PKC beta 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.
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