Effects of the chemotherapeutic agent doxorubicin on the protein C anticoagulant pathway.
Although chemotherapy treatment is associated with an increased risk of thrombosis, the pathogenic mechanisms for the thrombogenic effect of chemotherapeutic drugs are poorly understood. We hypothesize that exposure of vascular endothelial cells to chemotherapeutic agents results in the loss of a thromboresistant phenotype. In this study, we examined the effects of the chemotherapeutic agent doxorubicin on the endothelium-based protein C anticoagulant pathway. The endothelial cell protein C receptor (EPCR) and thrombomodulin are two endothelial cell surface receptors required for the conversion of zymogen protein C to the anticoagulant enzyme activated protein C. Exposure of human umbilical vein endothelial cells (HUVEC) to doxorubicin resulted in a dose- and time-dependent decrease in cell surface EPCR levels. This decrease occurred as a result of receptor shedding as well as from a down-regulation in EPCR mRNA levels. In contrast, doxorubicin treatment of HUVECs resulted in a dose- and time-dependent increase in cell surface thrombomodulin attributed to an up-regulation of thrombomodulin mRNA levels. The net effect of the doxorubicin-induced changes in EPCR and thrombomodulin levels was a decrease in the capacity of HUVECs to convert protein C to activated protein C. Preliminary studies suggest that doxorubicin free radical metabolites mediate the doxorubicin-induced changes in EPCR expression but not those of thrombomodulin expression. In summary, these results suggest that doxorubicin alters the hemostatic balance of endothelial cells by down-regulating the endothelium-based protein C anticoagulant pathway.
Woodley-Cook
Joel
J
Department of Medical Sciences, McMaster University, Canada.
Shin
Lucy Y Y
LY
Swystun
Laura
L
Caruso
Sonya
S
Beaudin
Suzanne
S
Liaw
Patricia C
PC
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D011486:Protein C / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018180:Thrombomodulin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D001779:Blood Coagulation Factors; D011486:Protein C; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018180:Thrombomodulin; C091963:activated protein C receptor; D004317:Doxorubicin