Cimetidine inhibits salivary gland tumor cell adhesion to neural cells and induces apoptosis by blocking NCAM expression

Masakatsu Fukuda,Hideaki Sakashita,Kaoru Kusama

doi:10.1186/1471-2407-8-376

Abstract

BackgroundCimetidine, 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.MethodsIn 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.ResultsWe 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-κB, a transcriptional activator of NCAM gene expression.ConclusionThese 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.

Highlights

Cimetidine, a histamine type-2 receptor antagonist, has been reported to inhibit the growth of glandular tumors such as colorectal cancer, the mechanism of action underlying this effect is unknown
We demonstrated previously [16] that neural cell adhesion molecule (NCAM) is spontaneously expressed in the human salivary gland tumor HSG cell line, derived from the submandibular salivary gland, and that HSG cell proliferation may be controlled via a homophilic (NCAMNCAM) binding mechanism
Aithough HSG cells and neural cells were further co-incubated with various concentrations of cimetidine (10-8 to 10-4 M) for 24 h, morphological change to apoptotic cells was not observed in neural cells

Summary

Introduction

Cimetidine, a histamine type-2 receptor antagonist, has been reported to inhibit the growth of glandular tumors such as colorectal cancer, 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 investigated the effects of cimetidine on growth and perineural/neural invasion of salivary gland tumor cells. Cimetidine may act by enhancing the host immune response against tumor cells [6,7] or by blocking the cell growth-promoting activity of histamine [5,8,9,10]. We demonstrated recently that cimetidine inhibited neural cell adhesion molecule (NCAM) expression and induced apoptosis in salivary gland tumor cells [12]. Facial paralysis due to perineural/neural invasion occurs so frequently that it is generally accepted as a hallmark of ACCs [13,14,15], and inhibition of perineural/neural invasion could be a strategy for arresting the development of ACC

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Conclusion