Cimetidine Preserves Non‐specific Immune Function After Colonic Resection for Cancer

Adams, Warwick J.; Morris, David L.; Ross, William; Lubowski, David Z.; King, D. W.; Peters, Lyndsay

doi:10.1111/j.1445-2197.1994.tb04562.x

Cited by 42 publications

(23 citation statements)

References 36 publications

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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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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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“…Administration of CIM has been found to preserve, to some degree, the patients' perioperative immunity [5,6] , to improve the survival of patients with colorectal cancer, melanoma, and renal cell cancer [7][8][9][10][11][12][13][14][15] . Although it is not clear whether this effect of CIM on cancer is direct or indirect, it has been proposed that CIM may act by enhancing the host immune response to tumor cells [16,17] or by blocking the cell growth-promoting activity of histamine in cancer cell lines [14,[16][17][18][19][20] . In this study, we used CIM in the perioperative period as an adjuvant immunomodulatory agent, and studied its effects on peripheral blood lymphocytes, NK cells and TIL in a randomized controlled clinical trial in patients with GI cancer.…”

Section: Introductionmentioning

confidence: 99%

Perioperative cimetidine administration promotes peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with gastrointestinal cancer: Results of a randomized controlled clinical trial

Cai¹,

Bai²,

Yuan³

et al. 2004

WJG

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AIM:To study the effects of perioperative administration of cimetidine (CIM) on peripheral blood lymphocytes, natural killer (NK) cells and tumor infiltrating lymphocytes (TIL) in patients with gastrointestinal (GI) cancer. METHODS:Forty-nine GI cancer patients were randomized into treatment group, who took CIM in perioperative period, and control group, who did not take the drug. The treatment was initiated 7 days before operation and continued for 10 days after surgery. At baseline examination before operation, on the 2nd and 10th postoperative days, total T lymphocytes, T helper cells, T suppressor cells, and NK cells in peripheral blood were measured respectively by immunocytochemical method using mouse-anti human CD 3 , CD 4 , CD 8 and CD 57 monoclonal antibodies. Blood samples from 20 healthy volunteers were treated in the same way as normal controls. Surgical specimens were examined during routine histopathological evaluation for the presence of TIL in tumor margin. Immunohistochemical study was performed to measure the proportion of T and B lymphocytes in TIL population. T and B lymphocytes were detected respectively using mouse-anti-human CD 3 and CD 20 monoclonal antibodies. RESULTS:In comparison with normal controls, both the treatment and control groups had decreased T cells, T helper cells and NK cells at baseline. In control group, total T cells, T helper cells and NK cells declined continuously with the disease progression and the decrease became more obvious after operation. From baseline to the 2nd postoperative day, the proportion of total T cells, T helper cells, and NK cells went down from 60.5±4.6% to 56.2±3.8%, 33.4±3.7% to 28.1±3.4%, and 15.0±2.8% to 14.2±2.2%, respectively. On the other hand, there were significant improvements in these parameters after CIM treatment. On the 10th postoperative day, the treatment group had significantly higher percentages of total T cells, T helper cells and NK cells than control group. Moreover, CIM treatment also boosted TIL response, as was reflected by findings that 68% (17/25) of the patients in treatment group had significant TIL responses and only 25% (6/24) of the cases had discernible TIL responses (P<0.01). CONCLUSION:Perioperative application of CIM to GI cancer patients could help restore the diminished cellular immunity induced by tumor burden and surgical maneuver. The drug could also boost TIL responses to tumor. These effects suggest that the drug be used as an immunomodulator for GI cancer patients.

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“…[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. The immune adjuvant effects of CIM have been confirmed by several other groups.…”

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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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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Cimetidine Preserves Non‐specific Immune Function After Colonic Resection for Cancer

Cited by 42 publications

References 36 publications

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

Perioperative cimetidine administration promotes peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with gastrointestinal cancer: Results of a randomized controlled clinical trial

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

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