Cisplatin up‐regulates ICAM‐1 expression in endothelial cell via a NF‐κB dependent pathway

Abstract

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 pathophsiologic process of cisplatin-induced vascular toxicity and may be exploited for therapeutic advantage.

Suicidal gene therapy in an NF-κB-controlled tumor environment as monitored by a secreted blood reporter

“…22 Additional extrinsic factors commonly used in cancer therapy could potentially induce NF-κB activity. Ionizing radiation 23 as well as many chemotherapeutic drugs such as cisplatin, 35 doxorubicin, 36 taxol 37 gemcitabine, 38 and etoposide 39 are potent inducers of NF-κB activation. These therapeutic modalities could be easily applied to our inducible gene therapy system to achieve a targeted and more efficient transgene expression.…”

Cisplatin Reduces Endothelial Cell Migration Via Regulation of Type 2-Matrix Metalloproteinase Activity

“…In addition, cisplatin exerts other actions independent of DNA adduct production which have important consequences in the cell function. For example, cisplatin increases Cdk2 activity in mouse kidney proximal tubule cells which regulates G2-M phase cellcycle progression [22] or promotes leukocytes adhesion to endothelial cells by stimulating ICAM-1 expression via a NF-κB-dependent pathway [23]. However, little is known about the role of cisplatin in the regulation of endothelial cell migration, a critical cell event necessary for angiogenesis, tissue remodeling and wound healing, as well as for the growth and metastasis of many tumors [24].…”

Vascular damage in testicular cancer patients: A study on endothelial activation by bleomycin and cisplatin in vitro

“…Up-regulation of ICAM-1 was also demonstrated in a rat model of bleomycininduced pulmonary fibrosis (41) and in primary human pulmonary micro-vascular endothelial cells (HMVEC-L) after exposure to bleomycine (42). Cisplatin up-regulated ICAM-1 in human umbilical vein endothelial cells (HUVECs) (43) and in a rat model of cisplatin-induced nephrotoxicity renal ICAM-1 mRNA levels were increased after exposure to this drug, while monoclonal anti-ICAM antibodies protected from renal dysfunction following cisplatin administration (44). We previously reported increased levels of the inflammation markers fibrinogen and high-sensitivity C-reactive protein in testicular cancer patients a median of seven years after cisplatin-based chemotherapy (7).…”