Cimetidine induces apoptosis of human salivary gland tumor cells

Abstract

It has been reported that cimetidine, a histamine type-2 receptor (H2R) antagonist, inhibits the growth of glandular tumors such as colorectal cancer. However, its effects against salivary gland tumors are still unknown. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express the neural cell adhesion molecule (NCAM) and also that HSG cell proliferation could be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. In the present study, we investigated the effects of cimetidine via the expression of NCAM on tumor growth and perineural/neural invasion in salivary gland tumor cells. Expression of both NCAM mRNA and protein was found to decrease in a dose-dependent manner upon treatment with cimetidine for 24 h. The MTT assay and confocal laser microscopy clearly showed that HSG cells underwent apoptosis after treatment with cimetidine. Activation of caspases 3, 7, 8 and 9 was observed in HSG cells after cimetidine treatment, thus confirming that the apoptosis was induced by the activated caspases. Apaf-1 activity was also detected in HSG cells in a dose-dependent manner after treatment with cimetidine. We also found that the cimetidinemediated down-regulation of NCAM expression in HSG cells did not occur via blocking of the histamine receptor, even though H2R expression was observed on HSG cells, as two other H2R antagonists, famotidine and ranitidine, did not show similar effects. We demonstrated for the first time that cimetidine can induce significant apoptosis of salivary gland tumor cells, which express NCAM, at least in part by downregulation of NCAM expression on the cells. These findings suggest that the growth, development and perineural/neural invasion of salivary gland tumor cells can be blocked by cimetidine administration through down-regulation of NCAM expression, as well as induction of apoptosis.

Cimetidine induces apoptosis in gastric cancer cells in vitro and inhibits tumor growth in vivo

“…A multicenter, randomized, double-blind, placebo-controlled study carried out by Tønnesen et al (14) on 181 patients showed that a post-operative course of cimetidine at a normal therapeutic dosage significantly prolonged the survival of gastric cancer patients. Although the cell-killing mechanism of cimetidine has been suggested (21,22), little is known of the effects of this compound on the growth of gastric cancer cells. This study, therefore, examined whether or not cimetidine induced apoptosis in gastric cancer cells and the mechanism related to cell death.…”

“…It was demonstrated that cimetidine inhibited the proliferation of human colorectal cancer cells and induced apoptosis in vitro (21). Recent experimental evidence also indicated that cimetidine inhibited NCAM expression and induced apoptosis of human salivary gland tumor cells (22,23). However, it was not previously determined whether cimetidine modulates the apoptotic pathway in gastric cancer cells.…”

Prognostic implications of cimetidine on advanced serous ovarian carcinoma related to cyclooxygenase-2 expression

“…On the other hand, cimetidine has been reported to inhibit histamine-induced angiogenesis (11) as well as epidermal growth factor-induced cell signaling (14). Cimetidine is also reported to induce apoptosis of human salivatory gland tumor cells (15). Notably, cimetidine improved the survival of patients whose ovarian cancer overexpressed COX-2.…”

Integrative genomic analyses of the histamine H1 receptor and its role in cancer prediction

“…Histamine is involved in cell proliferation, and key events in tumor development and progression have been extensively investigated (8,9). It has been found that H1R stimulates proliferation of breast carcinoma, melanoma and astrocytoma tumor cells (10)(11)(12). In this context, the investigation of H1R and its antagonists support a clear rationale for future supportive anticancer therapies.…”