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.

CDO1 promoter methylation is associated with gene silencing and is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients

“…One molecular mechanism of DTX causing endothelial dysfunction is DTX-induced ROS formation. [29][30][31][32][33] Here, low CDO1 methylation may be a useful marker to stratify patients for DTX treatment comparable to anthracycline treatment in breast cancer patients. 7 However, this is highly speculative and further studies are needed to test this hypothesis.…”

Intriguing Relationships Between Cancer and Systemic Sclerosis: Role of the Immune System and Other Contributors

“…Recently, the first case of scleroderma secondary to docetaxel with organ involvement (PAH and renal scleroderma crisis) has been published (131). One of the explanations would be the possibility of endothelial cell damage induced by oxidative stress secondary to docetaxel (132).…”

Docetaxel-Induced Systemic Sclerosis with Internal Organ Involvement Masquerading as Congestive Heart Failure

“…It has been hypothesized that PAH in systemic sclerosis occurs as a consequence of progressive remodeling of pulmonary vasculature with inflammation and endothelial injury as common precursors. A recent study revealed that docetaxel facilitates endothelial injury through oxidative stress mechanism [ 12 ]. Thus, docetaxel may induce PAH either by oxidative injury to the endothelial cells or by stimulating fibroblast cells as mentioned earlier.…”