Cisplatin up-regulates ICAM-1 expression in endothelial cell via a NF-kappaB dependent pathway.
The anticancer drug cis-diammindichloroplatin (cisplatin) can cause severe side-effects, but to date, the mechanisms of action of these dangerous side-effects have not been completely elucidated. Since cellular adhesion molecules (CAMs), by mediating the recruitment of circulating leukocytes to the blood vessel wall and their subsequent migration into the subendothelial spaces, play a crucial role in several pathophysiologic processes, we sought potential proof for CAMs in the pathophysiology of cisplatin-induced vascular damage. In vitro, human umbilical vein endothelial cells (HUVECs) were subjected to various concentrations of cisplatin, considerable up-regulation of intercellular adhesion molecule-1 (ICAM-1) but not P-selectin, E-selectin, and vascular cell adhesion molecule 1 at both messenger mRNA and protein expression levels were observed. Electrophoretic mobility shift assays and Western blotting analysis revealed that cisplatin up-regulates ICAM-1 expression in HUVECs via an NF-kappaB-dependent pathway. Further intravital microscopy study demonstrated that significantly higher (P < 0.01) numbers of rolling and sticking leukocytes on the wall of postcapillary venules in male Golden Syrian hamster's cheek pouch bearing a human cervical carcinoma were observed, while inhibition of ICAM-1 by using specific anti-ICAM-1 antibody can attenuate cisplatin-stimulated leukocyte/endothelium interactions. These data suggest that ICAM-1 involves in the pathophisiologic process of cisplatin-induced vascular toxicity and may be exploited for therapeutic advantage.
Yu
Minghua
M
Institute of Microcirculation, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.
Han
Jianqun
J
Cui
Peilin
P
Dai
Min
M
Li
Hongwei
H
Zhang
Jian
J
Xiu
Ruijuan
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D006224:Cricetinae; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D007962:Leukocytes; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D016328:NF-kappa B; D010455:Peptides; C118258:SN50 peptide; D018799:Intercellular Adhesion Molecule-1; D002945:Cisplatin