Paclitaxel impairs endothelial cell adhesion but not cytokine-induced cellular adhesion molecule expression.
Local delivery of antiproliferative agents using drug-eluting stents has become a productive area of research for preventing in-stent restenosis. Recently, the microtubule stabilizing drug paclitaxel has been used to coat stents. While the actions of paclitaxel on smooth muscle are well documented, effects on endothelial cells (ECs) are largely unknown. Nevertheless, restoration of EC function is a critical step in repairing the vascular lesion. We assessed the effects of paclitaxel by examining three events that are critical in controlling the severity of vascular injury: (1) adhesion of ECs to matrix proteins, (2) EC migration, and (3) cytokine-stimulated cellular adhesion molecule (CAM) expression on the surface of ECs. Paclitaxel inhibited both EC adhesion and migration of ECs; however, it had no effect on tumor necrosis-stimulated CAM expression on ECs. The mechanisms of paclitaxel action on matrix adhesion and migration are not clear, but protein kinase C and myosin light chain kinase do not appear to play a role as they are unaffected by treatment of the cells with paclitaxel. On the other hand, the MAP kinase ERK1/2 is modestly inhibited by paclitaxel. While paclitaxel-coated endovascular stents may prevent smooth muscle proliferation, their attenuation of EC migration and adhesion to the lesion coupled with an inability to reduce cytokine-induced CAM expression on ECs may limit their effectiveness.
Davis
Harold W
HW
Division of Vascular Surgery, University of Cincinnati Medical Center, Cincinnati, OH 45267-0558, USA. harold.davis@uc.edu
VandenBerg
Elizabeth
E
Reid
Maria D
MD
Roy-Chaudhury
Prabir
P
Edwards
John D
JD
D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009219:Myosin-Light-Chain Kinase / Q000502:physiology; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D011494:Protein Kinases; D011493:Protein Kinase C; D009219:Myosin-Light-Chain Kinase; D017239:Paclitaxel; D015739:Nocodazole