Anti-tumor effect of cimetidine via inhibiting angiogenesis factors in N-butyl-N-(4-hydroxybutyl) nitrosamine-induced mouse and rat bladder carcinogenesis

Chihara,

doi:10.3892/or_00000401

Cited by 12 publications

(4 citation statements)

References 21 publications

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“…The animal model of bladder cancer induction by BBN have been used in many studies [29][30][31][32][33] mainly because BBN induced alterations in the bladder of rodents that are correspondent to histopathological and molecular features of human transitional cell carcinoma [34][35][36]. In this work, bladder cancer was induced by the addition of 0.05 % of BBN in the drinking water for 4,8,12,18, and 24 weeks with a respective control group for each induction time.…”

Section: Bladder Cancer Inductionmentioning

confidence: 99%

NTPDase3 and ecto-5′-nucleotidase/CD73 are differentially expressed during mouse bladder cancer progression

Rockenbach

Braganhol

Dietrich

et al. 2014

Purinergic Signalling

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According to the World Health Organization, bladder cancer is the seventh most common cancer among men in the world. The current treatments for this malignancy are not efficient to prevent the recurrence and progression of tumors. Then, researches continue looking for better therapeutic targets which can end up in new and more efficient treatments. One of the recent findings was the identification that the purinergic system was involved in bladder tumorigenesis. The ectonucleotidases, mainly ecto-5′-nucleotidase/CD73 have been revealed as new players in cancer progression and malignity. In this work, we investigated the NTPDase3 and ecto-5′-nucleotidase/CD73 expression in cancer progression in vivo. Bladder tumor was induced in mice by the addition of 0.05 % of N-butyl-N-(hydroxybutyl)-nitrosamine (BBN) in the drinking water for 4, 8, 12, 18, and 24 weeks. After this period, mice bladders were removed for histopathology analysis and immunofluorescence assays. The bladder of animals which has received BBN had alterations, mainly inflammation, in initial times of tumor induction. After 18 weeks, mice's bladder has developed histological alterations similar to human transitional cell carcinoma. The cancerous urothelium, from mice that received BBN for 18 and 24 weeks, presented a weak immunostaining to NTPDase3, in contrast to an increased expression of ecto-5′-nucleotidase/CD73. The altered expression of NTPDase3 and ecto-5′-nucleotidase/ CD73 presented herein adds further evidence to support the idea that alterations in ectonucleotidases are involved in bladder tumorigenesis and reinforce the ecto-5′-nucleotidase/ CD73 as a future biomarker and/or a target for pharmacological therapy of bladder cancer.

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Section: Bladder Cancer Inductionmentioning

confidence: 99%

NTPDase3 and ecto-5′-nucleotidase/CD73 are differentially expressed during mouse bladder cancer progression

Rockenbach

Braganhol

Dietrich

et al. 2014

Purinergic Signalling

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“…The antitumor effect of cimetidine has been suggested to involve various mechanisms underlying its beneficial effects in patients with cancer. In addition to its immunomodulatory effects, cimetidine exerts antitumor activity by inhibiting cancer cell proliferation by blocking histamine receptors [ 24 ], affecting histamine metabolism [ 25 ], blocking the expression of E-selectin to inhibit cancer cell adhesion and prevent metastasis [ 26 ], and inhibiting angiogenesis [ 27 , 28 ]. In our results, cimetidine had mild antitumor activity, but significantly attenuated the antitumor effect of anti-PD-L1 without major toxicity.…”

Section: Discussionmentioning

confidence: 99%

Cimetidine Attenuates Therapeutic Effect of Anti-PD-1 and Anti-PD-L1 and Modulates Tumor Microenvironment in Colon Cancer

Kuo,

Lai,

Shieh

et al. 2024

Biomedicines

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Histamine modulates immunity by binding to histamine receptor 2 (H2R). Cimetidine, an H2R antagonist that inhibits gastric acid secretion and treats gastrointestinal ulcers, interferes with histamine-mediated immunomodulation and may have anticancer activity. This study examined cimetidine’s effect on the anticancer effect of anti-PD-L1 in colon cancer. The MTT assay, colony formation assay, and DNA histograms assessed cell viability, clonogenicity, and cell cycle distribution, respectively. Flow cytometry measured H2R and PD-L1 expression and estimated specific immune cell lineages. For the in vivo study, tumor cells were subcutaneously implanted into the right flank of BALB/c mice. Cimetidine had no significant effect on CT26 cell viability, clonogenicity, or cell cycle distribution. It also did not affect H2R and PD-L1 expression levels in CT26 cells. In vivo, anti-PD-1 and anti-PD-L1 suppressed CT26 tumor growth, whereas cimetidine showed mild antitumor activity. In the combined experiment, cimetidine significantly attenuated anti-PD-1 and anti-PD-L1′ antitumor effects without major toxicity. In the tumor microenvironment, anti-PD-L1 increased CD3+ T, CD4+ T, and CD8+ T cells and M1 macrophages. Combined treatment with cimetidine reversed this. Cimetidine also reversed anti-PD-1 and anti-PD-L1′s decrease in circulating and tumor-associated neutrophils. Cimetidine attenuated anti-PD-L1′s antitumor effect and modulated the tumor microenvironment in colon cancer.

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“…Additional study of CRC reported that histamine significantly augmented cell proliferation and VEGF production via a COX-2 cascade, and administration of cimetidine notably inhibited this effect [180]. Cimetidine also revealed antitumor activity via inhibiting several angiogenesis factors such as VEGF and platelet-derived endothelial growth factor in chemically-induced bladder carcinogenesis in mice and rats [181]. The potential action mechanisms underlying the antitumor effects of cimetidine are illustrated in Figure 3.…”

Section: Histamine H2 Receptormentioning

confidence: 98%

Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets

Nguyen

Cho

2021

Biomolecules

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High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine and its cognate receptors in cancer biology. We also discuss the novel therapeutic approaches of selective HR ligands and their potential prognostic values in cancer treatment. Briefly, histamine is highly implicated in cancer development, growth, and metastasis through interactions with distinct HRs. It also regulates the infiltration of immune cells into the tumor sites, exerting an immunomodulatory function. Moreover, the effects of various HR ligands, including H1R antagonists, H2R antagonists, and H4R agonists, on tumor progression in many different cancer types are described. Interestingly, the expression levels of HR subtypes may serve as prognostic biomarkers in several cancers. Taken together, HRs are promising targets for cancer treatment, and HR ligands may offer novel therapeutic potential, alone or in combination with conventional therapy. However, due to the complexity of the pathophysiological roles of histamine and HRs in cancer biology, further studies are warranted before HR ligands can be introduced into clinical settings.

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Anti-tumor effect of cimetidine via inhibiting angiogenesis factors in N-butyl-N-(4-hydroxybutyl) nitrosamine-induced mouse and rat bladder carcinogenesis

Cited by 12 publications

References 21 publications

NTPDase3 and ecto-5′-nucleotidase/CD73 are differentially expressed during mouse bladder cancer progression

NTPDase3 and ecto-5′-nucleotidase/CD73 are differentially expressed during mouse bladder cancer progression

Cimetidine Attenuates Therapeutic Effect of Anti-PD-1 and Anti-PD-L1 and Modulates Tumor Microenvironment in Colon Cancer

Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets

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