A novel anticancer effect of thalidomide: inhibition of intercellular adhesion molecule-1-mediated cell invasion and metastasis through suppression of nuclear factor-kappaB.
OBJECTIVE
Thalidomide has been reported to have antiangiogenic and antimetastatic effects. Intercellular adhesion molecule-1 (ICAM-1) was shown to be involved in monocyte adherence to epithelial cells and cancer cell invasion. In this study, we further investigated the role of ICAM-1 in tumorigenesis, including tumor formation and metastasis. ICAM-1 as a molecular target for cancer and the anticancer effect of thalidomide were investigated.


METHODS
Expression of ICAM-1 protein in human lung cancer specimens was assessed by immunohistochemistry. ICAM-1 overexpressing A549 cells (A549/ICAM-1) were established to investigate the direct effect of ICAM-1 on in vitro cell invasion and in vivo tumor metastasis. Transient transfection and luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation were done to assess the activity and binding of nuclear factor-kappaB to the ICAM-1 promoter. A xenograft model in nude mice was conducted to evaluate the anticancer effect of thalidomide.


RESULTS
High expression of ICAM-1 in human lung cancer specimens was correlated with a greater risk of advanced cancers (stages III and IV). A549/ICAM-1 cells were shown to induce in vitro cell invasion and in vivo tumor metastasis. Anti-ICAM-1 antibody and thalidomide had inhibitory effect on these events. Thalidomide also suppressed tumor necrosis factor-alpha-induced ICAM-1 expression through inhibition of nuclear factor-kappaB binding to the ICAM-1 promoter. The in vivo xenograft model showed the effectiveness of thalidomide on tumor formation.


CONCLUSIONS
These studies provide a framework for targeting ICAM-1 as a biologically based therapy for cancer, and thalidomide might be effective in human lung cancer.
Lin
Yi-Chu
YC
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Shun
Chia-Tung
CT
Wu
Ming-Shiang
MS
Chen
Ching-Chow
CC
D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary* / Q000601:surgery; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary* / Q000601:surgery; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D013329:Structure-Activity Relationship; D013792:Thalidomide / Q000008:administration & dosage / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000970:Antineoplastic Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D013792:Thalidomide