Cimetidine: An Immunomodulator

Kumar, Ashir

doi:10.1177/106002809002400316

Cited by 29 publications

(15 citation statements)

References 45 publications

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“…Kumar, A. reported that suppressive T lymphocytes possess histamine2 (H2) receptors and contribute significantly to the function of immune system. 11 Jutel M et al proposed that histamine, through its H2 receptor, positively interferes with the peripheral antigen tolerance that is induced by regulatory T cells via several pathways. 33 However, it is uncertain whether histamine is also involved in CIM-stimulated Foxp3 reduction.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Early studies had shown that CIM is capable of inhibiting suppressor cell effector function 7 and expansion 8 and that regulatory T cells possess the H2 receptor. [9][10][11] Experimentally, CIM has been shown to enhance a variety of immunologic functions both in vivo and in vitro, including decrease in the relative abundance or function of Treg cells in several studies. [12][13][14] Indeed, Wang J et al 14 reported that the use of CIM as a vaccine adjuvant in mice could induce expression of pro-inflammatory cytokines such as IL-6 and IL-12 and down-regulate expression of anti-inflammatory cytokines, including IL-10 and TGF-b.…”

Section: Introductionmentioning

confidence: 99%

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Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells

Zhang

Chen

Luo

et al. 2016

Human Vaccines & Immunotherapeutics

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Foxp3-expressing Treg cells have been well documented to provide immune regulation by promoting immune tolerance and suppressing immune over-reaction. Cimetidine (CIM), used to inhibit stomach acid secretion, has been reported to promote immune responses and suppress Treg cell function in several studies. However, the underlying mechanism is unknown. To investigate CIM effects on the suppressive function of Treg and Foxp3, here we used CIM to stimulate human CD4 C CD25 C Treg cells and Jurkat T cells and evaluated changes of Foxp3 expression and stability. Our data showed that CIM leads to a reduction of Foxp3 via E3 ligase Stub1-mediated proteosomal degradation, which is dependent on an activated PI3K-AKTmTOR pathway. Thus, CIM affects the suppressive function of Treg cells by destabilizing their Foxp3 expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells

Zhang

Chen

Luo

et al. 2016

Human Vaccines & Immunotherapeutics

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“…However, the exact mechanism by which cimetidine may exert an anticancer effect remains uncertain. cimetidine is thought to exert its effect by blocking high peritumoral concentrations of histamine and increasing systemic immunoreactivity via H 2 receptor antagonism of circulating T suppressor cells or maintenance of natural killer cell activity (19)(20)(21). However, Rajendra et al (22) have demonstrated that cimetidine has a direct antiproliferative effect in the absence of histamine type 2 receptors and the induction of apoptosis.…”

Section: Cimetidine Inhibits the Growth Of Transplantable Tumorsmentioning

confidence: 99%

Cimetidine inhibits the adhesion of gastric cancer cells expressing high levels of sialyl Lewis x in human vascular endothelial cells by blocking E-selectin expression

2011

Int J Mol Med

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Abstract. cimetidine has been shown to have anti-metastatic activity and improves the survival of patients with colorectal cancer. One hypothesis is its modulation of the expression of the cell adhesion molecule by target organ endothelial cells. Because of the inconclusive results in clinical trials of gastric cancer, we investigated the effects of cimetidine on the adhesion of gastric cancer cells to activated endothelial cells and on the expression of some cell adhesion molecules. Human endothelial cells were pre-incubated with cimetidine for 6 h, incubated with the cytokine tumor necrosis factor for 4 h, and the endothelial surface expression of E-selectin was evaluated by flow cytometry, immunostaining and ELISA. Further, we investigated E-selectin mRNA expression by RT-PcR. Three gastric cancer cell lines (SGC-7901, MGC-803, BGC-823) and a normal gastric epithelial cell line, GES-1, were studied for the surface expression of sialyl Lewis x by flow cytometry and immunostaining. Adherence of CFSE-labeled gastric cancer cells and GES-1 cells to endothelial cell monolayers was determined. Cimetidine significantly reduced E-selectin expression of activated endothelial cells, but did not influence E-selectin expression at the mRNA level. Three gastric cancer cell lines expressed high levels of sialyl Lewis x, whereas GES-1 did not. Cimetidine also significantly decreased gastric cancer cell adherence to stimulated endothelial cells. The inhibition of E-selectin expression corresponded to the reduction of tumor cell adherence. The effects of cimetidine on tumor adhesion were almost nullified by pre-incubation with E-selectin and sialyl Lewis x antibody. Furthermore, there was no significant change of GES-1 adherence to endothelial cells by TNF-α, cimetidine, E-selectin and sialyl Lewis x antibody. The inhibiton of gastric cancer cell adherence to cytokinestimulated endothelial cells treated with cimetidine appears to result from blocking endothelial E-selectin expression. These data support the hypothesis that cimetidine may exert its anti-metastatic effects in gastric cancer, in part, by inhibiting E-selectin/sialyl Lewis x-mediated adherence of gastric cancer cells to endothelial cells in the metastasis target organs.

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“…Several studies have suggested various mechanisms underlying the beneficial effect of cimetidine on cancer patients, such as the following: (i) reversal of the pharmacological activity of histamine, tumour growth promoter by blocking histamine receptors on cancer cells Reynolds et al, 1996) or affecting histamine metabolism (Garcia-Caballero et al, 1994); (ii) acting as an antioxidant, thus inhibiting tumour growth (Kimura et al, 1986) and (iii) augmentation of anticancer immune reactivity through receptor antagonism of circulatory suppressor T cells (Kumar, 1990), prevention of postoperative alterations of lymphocyte subpopulations (Hansbrough et al, 1986), or by maintenance of natural killer cell activity (Katoh et al, 1996). In our study, we found that cimetidine could block the expression of E-selectin on the surface of human umbilical vein endothelial cells, thus blocking the tumour cell adhesion to endothelium and preventing the liver metastasis in nude mice model (Kobayashi et al, 2000).…”

mentioning

confidence: 99%

Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells

et al. 2002

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Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day 71 of cimetidine orally together with 200 mg day 71 of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P50.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sL x ) and A (sL a ). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sL x and sL a antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sL x , of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sL x and sL a .

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Cimetidine: An Immunomodulator

Cited by 29 publications

References 45 publications

Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells

Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells

Cimetidine inhibits the adhesion of gastric cancer cells expressing high levels of sialyl Lewis x in human vascular endothelial cells by blocking E-selectin expression

Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells

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