The protective effects of paclitaxel on platelet aggregation through the inhibition of thromboxane A2 synthase.
Paclitaxel is an anticancer drug used in the treatment of ovarian, breast, head and neck, lung, and prostate cancer. We investigated the antiplatelet activity of paclitaxel in vitro as well as a possible antiplatelet mechanism. Paclitaxel inhibited washed rabbit platelet aggregation induced by collagen in a concentration dependent manner, with an IC(50) of 59.7 +/- 3.5. However, it had little effect on platelet aggregation mediated by arachidonic acid, U46619, a thromboxane (TX) A(2) mimic, or thrombin, suggesting that paclitaxel may strongly inhibit collagen mediated signal transduction. In accordance with these findings, paclitaxel blocked collagen induced cytosolic calcium mobilization, arachidonic acid liberation, and serotonin secretion. In addition, it inhibited arachidonic acid mediated platelet aggregation by about 37% by interfering with TXA(2) synthase as measured by the formation of arachidonic acid mediated TXA(2) and prostaglandin D(2), as well as cyclooxygenase-1 and TXA(2) synthase activity assays. Taken together, these results point to a cellular mechanism for the antiplatelet activity of paclitaxel through the inhibition of TXA(2) synthase and cytosolic calcium mobilization. This may contribute to the beneficial effects of paclitaxel on the cardiovascular system.
Lee
Jung-Jin
JJ
Department of Pharmacology, Chungnam National University College of Pharmacy, Daejeon, 305-764, Korea.
Yu
Ji-Yeon
JY
Lee
Joo-Hyung
JH
Zhang
Wei Yun
WY
Kim
Tack-Joong
TJ
Myung
Chang-Seon
CS
Yun
Yeo-Pyo
YP
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D002118:Calcium / Q000097:blood; D003094:Collagen / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D051966:Phospholipase C gamma / Q000097:blood; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000097:blood; D011817:Rabbits; D012701:Serotonin / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000378:metabolism; D013928:Thromboxane A2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000097:blood; D013997:Time Factors
D004791:Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D012701:Serotonin; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003094:Collagen; D051545:Cyclooxygenase 1; D051966:Phospholipase C gamma; D013917:Thrombin; D013930:Thromboxane-A Synthase; D017239:Paclitaxel; D015230:Prostaglandin D2; D002118:Calcium