Cimetidine inhibits salivary gland tumor cell adhesion to neural cells and induces apoptosis by blocking NCAM expression.
BACKGROUND
Cimetidine, a histamine type-2 receptor antagonist, has been reported to inhibit the growth of glandular tumors such as colorectal cancer, however the mechanism of action underlying this effect is unknown. Adenoid cystic carcinoma is well known as a malignant salivary gland tumor which preferentially invades neural tissues. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express neural cell adhesion molecule (NCAM), that HSG cell proliferation may be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. We further demonstrated that cimetidine inhibited NCAM expression and induced apoptosis in HSG cells. Here, we investigated the effects of cimetidine on growth and perineural/neural invasion of salivary gland tumor cells.


METHODS
In this study, we have examined the effect of cimetidine on cancer cell adhesion to neural cells in vitro, one of the critical steps of cancer invasion and metastasis. We have also used an in vivo carcinogenesis model to confirm the effect of cimetidine.


RESULTS
We have demonstrated for the first time that cimetidine can block the adhesion of HSG cells to neural cell monolayers and that it can also induce significant apoptosis in the tumor mass in a nude mouse model. We also demonstrated that these apoptotic effects of cimetidine might occur through down-regulation of the cell surface expression of NCAM on HSG cells. Cimetidine-mediated down-regulation of NCAM involved suppression of the nuclear translocation of NF-kappaB, a transcriptional activator of NCAM gene expression.


CONCLUSIONS
These findings suggest that growth and perineural/neural invasion of salivary gland tumors can be blocked by administration of cimetidine via induction of apoptosis and in which NCAM plays a role.
Fukuda
Masakatsu
M
Second Division of Oral and Maxillofacial Surgery, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283, Japan. fukudam@dent.meikai.ac.jp
Kusama
Kaoru
K
Sakashita
Hideaki
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects*; D002927:Cimetidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000187:drug effects; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D019006:Neural Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000473:pathology; D012468:Salivary Gland Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D014407:Tumor Cells, Cultured
D006635:Histamine H2 Antagonists; D016328:NF-kappa B; D019006:Neural Cell Adhesion Molecules; D002927:Cimetidine