Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells

Zheng, Yisheng; Xu, Meng; Xiao, Li; Jia, Jun; Fan, Kexing; Lai, Guoxiang

doi:10.1016/j.molimm.2012.10.035

Cited by 63 publications

(40 citation statements)

References 37 publications

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“…An accumulating body of evidence suggests that this drug may improve the survival of patients with different malignancies, and its antitumor effect is mediated at least in part by immune mechanisms. In particular, cimetidine-mediated immunomodulation is based on the the enhancement of antigen-presenting DC activity, 113 inhibition of suppressor T lymphocyte activity 114 and MDSC activity, 115 stimulation of NK cell activity 116 and increase in IL-2 production in helper T lymphocytes. 117 Another H2-antagonist famotidine has been found to stimulate IL-2-driven LAK activity beneficial for the treatment of renal cancer.…”

Section: Inhibitors Of Indoleamine 23-dioxygenase (Ido)mentioning

confidence: 99%

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

Селедцов

Гончаров

Селедцова

2015

Human Vaccines & Immunotherapeutics

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Section: Inhibitors Of Indoleamine 23-dioxygenase (Ido)mentioning

confidence: 99%

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

Селедцов

Гончаров

Селедцова

2015

Human Vaccines & Immunotherapeutics

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“…It has been demonstrated to inhibit tumor growth by several underlying mechanisms, including the inhibition of cancer cell proliferation (20), the blockade of tumor angiogenesis (15) and the enhancement of immune activity (26). A previous study demonstrated that cimetidine induced myeloid-derived suppressor cell apoptosis in mice (27). These results suggested that cimetidine directly suppresses tumor growth via various antitumor effects and indirectly via specific modifications of the tumor microenvironment, including angiogenesis, and of the host immune responses.…”

Section: Discussionmentioning

confidence: 99%

Repurposing cimetidine for cholangiocarcinoma: Antitumor effects in vitro and in vivo

et al. 2017

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Abstract. Cimetidine is a histamine type-2 (H 2 ) receptor antagonist that has been demonstrated to have antitumor effects on various types of malignancy. However, its effect on cholangiocarcinoma (CCA), a chemotherapy-resistant bile duct tumor, has yet to be investigated. In the present study, the antitumor activity of cimetidine in vitro and in vivo was evaluated. A methylthiotetrazole assay revealed that the proliferation of certain CCA cell lines was inhibited by cimetidine, which induced the caspase-dependent apoptosis of CCA cells via suppression of the protein kinase B signaling pathway. Suppression of Akt phosphorylation, caspase-3, -8 and -9 activation, phosphotidylserine exposure determined by Annexin V binding assay and the presence of a sub-G1 population were demonstrated by western blotting and flow cytometry analysis. In a CCA xenograft mouse model cimetidine inhibited the growth of CCA cells without observable adverse effects. These results suggest that cimetidine has the potential to be an effective antitumor agent for the treatment of CCA. IntroductionCholangiocarcinoma (CCA) is a highly lethal type of cancer that arises from the bile duct epithelium (1). Although CCA is a rare form of cancer, the global incidence of CCA is increasing, particularly that of the intrahepatic subtype (2). However, the highest incidence of CCA has been reported in the northeast of Thailand where the carcinogenic liver fluke Opisthorchis viverrini is considered a causative agent (3). The early diagnosis of CCA is challenging as patients with CCA typically have non-specific symptoms, and CCA tumor markers are yet to be developed (4). The majority of patients with CCA present with a late-stage disease that is frequently inoperable, and the outcomes of conventional chemotherapy or radiotherapy are unsatisfactory (5). Therefore, a unique approach to developing novel targeting therapies is required to reduce CCA-associated mortality.Cimetidine is an antagonist of histamine type-2 (H 2 ) receptors and is indicated for patients with gastro-esophageal reflux diseases, peptic ulcers or hypersecretory conditions (6,7). The effect of cimetidine on the survival of patients has been reported in various types of cancer, including gastric cancer (8), colorectal cancer (6,9,10), renal cell carcinoma (11), malignant melanoma (12) and glioblastoma (13). Numerous molecular mechanisms underlying the anticancer activities of cimetidine have been revealed, including the inhibition of cell proliferation by blocking the cell growth-promoting effect of histamine (14), the inhibition of tumor angiogenesis (15), the stimulation host immune responses (16) and the suppression of cell adhesion (17). However, the effects of cimetidine in CCA have yet to be demonstrated.In the present study, the anti-CCA activity of cimetidine was examined and the antiproliferative and apoptosis-inducing effects of cimetidine were determined. This was revealed to be partially due to the suppression of protein kinase B (Akt) phosphorylation. A CCA transplant xenogra...

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“…Cimetidine, a histamine type-2 receptor antagonist, reduced CD11b + Gr-1 + MDSC accumulation in spleen, blood and tumor tissue of 3LL-bearing mice and reversed MDSC-mediated T-cell suppression by impairing NO production and ARG1 expression in MDSCs, inducing Fas/FasL expression on MDSC surface, and hence fuelling a caspasedependent apoptosis pathway [164]. Very recently, the evidence that histamine is important in MDSC trafficking and activation was supported by a study showing not only that MDSCs express histamine receptors HR1-3, but also that blockade of these receptors by HR1 or HR2 antagonists reversed the histamine enhancement of MDSC survival and proliferation observed in cell culture [165].…”

Section: Targeting Mdsc Developmentmentioning

confidence: 99%

MDSCs in cancer: Conceiving new prognostic and therapeutic targets

Sanctis

Solito

Ugel

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells

Cited by 63 publications

References 37 publications

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

Repurposing cimetidine for cholangiocarcinoma: Antitumor effects in vitro and in vivo

MDSCs in cancer: Conceiving new prognostic and therapeutic targets

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