Histamine H4 receptor signalling in tongue cancer and its potential role in oral carcinogenesis - a short report (original) (raw)
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Inflammation Research, 1997
Objective: In the present work we studied the association of histamine receptors with second messengers during multistage carcinogenesis in Sencar mice skin. Methods: 96 Sencar female mouse, divided into six groups were used. Tumors appeared only in the 7,12-dimethylbenz[a]anthracene-initiated and 12-O-tetradecanoylphorbol-13-acetate-promoted group. Control groups received only TPA, or acetone or no treatment at all. Periodically during the promotion period, cAMP and inositol phosphate production were measured after stimulation with H 1 or H 2 agonists in samples from all groups. Results: In non-treated skin, H 1 receptors were coupled to phosphatidylinositol hydrolysis and H 2 receptors mediated cAMP production. Conversely, in tumors H 2 receptors were associated with phosphatidylinositol hydrolysis and H 1 mediated a rise in cAMP levels. The skin among tumors and the skin from all control groups maintained the same coupling as non-treated skin. An increase in mast cell number, with a homogeneous subepithelial distribution and marked phenotypic changes, was also observed in promoted skin. Conclusions: These findings indicate an atypical association of histamine receptors with second messengers that could be a critical feature for the postulated action of histamine in tumor growth.
Pathophysiological Role of Histamine H4 Receptor in Cancer: Therapeutic Implications
Frontiers in Pharmacology, 2019
Cancer is a leading cause of death in both developed and developing countries. Although advances in cancer research lead to improved anti-neoplastic therapies, they continue to have unfavorable outcomes, including poor response and severe toxicity. Thus, the challenge for the new therapeutic approaches is to increase antitumor efficacy by targeting different molecules encompassed in the tumor and its microenvironment, as well as their specific interactions. The histamine H4 receptor (H4R) is the last discovered histamine receptor subtype and it modulates important immune functions in innate and in adaptive immune responses. Several ligands have been developed and some of them are being used in clinical trials for immune disorders with promising results. When searched in The Cancer Genome Atlas (TCGA) database, human H4R gene was found to be expressed in bladder cancer, kidney cancer, breast cancer, gastrointestinal cancers, lung cancer, endometrial cancer, and skin cancer. In the present work, we aimed to briefly summarize current knowledge in H4R's pharmacology and in the clinical use of H4R ligands before focusing on recent data reporting the expression of H4R and its pathophysiological role in cancer, representing a potential molecular target for cancer therapeutics. H4R gene and protein expression in different types of cancers compared with normal tissue as well as its relationship with patient prognosis in terms of survival will be described.
Cancer Biology & Therapy, 2008
There is increasing evidence that describes a histamine role in normal and cancer cell proliferation. To better understand the importance of histamine in breast cancer development, the expression of histamine H3 (H3R) and H4 (H4R) receptors and their association with proliferating cell nuclear antigen (PCNA), histidine decarboxylase (HDC) and histamine content were explored in mammary biopsies. Additionally, we investigated whether H3R and H4R were implicated in the biological responses triggered by histamine in MDA-MB-231 breast cancer cells. The expression levels of H3R, H4R, PCNA, HDC and histamine content were determined by immunohistochemistry in 40 benign and malignant lesions. MDA-MB-231 cells proliferation (clonogenic assay and BrdU incorporation) and cell cycle distribution (flow cytometry) were evaluated upon treatment with histamine, H3R and H4R agonists and antagonists. Apoptosis was determined by Annexin staining and TUNEL assay. Cell migration was assessed by transwell system. Results indicate that H3R was detected in 67% (10/15) of benign lesions and in almost all carcinomas (24/25), being the level of its expression significantly higher in carcinomas (p = 0.0016). The non-tumoral breast tissue surrounding carcinomas revealed a lower H3R expression compared to the tumor cells. Only 13% (2/15) of the benign lesions expressed H4R compared to 44% (11/25) of the carcinomas. Interestingly, H3R expression was correlated in carcinomas with the expression of HDC and PCNA (p < 0.0001), and also histamine content (p = 0.0229). Accordingly, histamine increased MDA-MB-231 cells proliferation and also migration via H3R. In contrast, activation of H4R inhibited proliferation and this effect was associated with an arrest in the G 0 /G 1 phase of the cell cycle and an induction of apoptosis. Present findings demon-strate the presence of H3R and H4R in human mammary tissue and suggest that H3R may be involved in the regulation of breast cancer growth and progression representing a novel molecular target for new therapeutic approach.
Histamine receptors and cancer pharmacology
British Journal of Pharmacology, 2010
Considerable evidence has been collected indicating that histamine can modulate proliferation of different normal and malignant cells. High histamine biosynthesis and content together with histamine receptors have been reported in different human neoplasias including melanoma, colon and breast cancer, as well as in experimental tumours in which histamine has been postulated to behave as an important paracrine and autocrine regulator of proliferation. The discovery of the human histamine H4 receptor in different tissues has contributed to our understanding of histamine role in numerous physiological and pathological conditions revealing novel functions for histamine and opening new perspectives in histamine pharmacology research. In the present review we aimed to briefly summarize current knowledge on histamine and histamine receptor involvement in cancer before focusing on some recent evidence supporting the novel role of histamine H4 receptor in cancer progression representing a promising molecular target and avenue for cancer drug development.
Histamine receptors and cancer pharmacology: Histamine receptors in cancer
British Journal of Pharmacology, 2010
Considerable evidence has been collected indicating that histamine can modulate proliferation of different normal and malignant cells. High histamine biosynthesis and content together with histamine receptors have been reported in different human neoplasias including melanoma, colon and breast cancer, as well as in experimental tumours in which histamine has been postulated to behave as an important paracrine and autocrine regulator of proliferation. The discovery of the human histamine H4 receptor in different tissues has contributed to our understanding of histamine role in numerous physiological and pathological conditions revealing novel functions for histamine and opening new perspectives in histamine pharmacology research. In the present review we aimed to briefly summarize current knowledge on histamine and histamine receptor involvement in cancer before focusing on some recent evidence supporting the novel role of histamine H4 receptor in cancer progression representing a promising molecular target and avenue for cancer drug development.LINKED ARTICLESBJP has previously published a Histamine themed issue (2009). To view this issue visit http://dx.doi.org/10.1111/bph.2009.157.issue-1
Autoregulation of McA-RH7777 Hepatoma Cell Proliferation by Histamine H3 Receptors
Journal of Pharmacology and Experimental Therapeutics, 2008
Previous studies have suggested that histamine (HA) acts as an autocrine growth factor. We have explored the modulation of cell proliferation by HA using McA-RH7777 hepatoma cells. High L-histidine decarboxylase (HDC) expression and HA synthesis were found in McA-RH7777 cells. Whereas extracellular HA reached submicromolar concentrations, intracellular levels were very low, indicating that HA was secreted by the cells. McA-RH7777 cells also express H 3-receptor (H 3 R) transcripts and proteins. Reverse transcriptase-polymerase chain reaction analysis detected only transcripts for the long isoform. Immunocytochemistry performed with a selective H 3 R antibody showed that most cells were immunoreactive. H 3 R binding sites (B max ϳ30 fmol/mg protein) were identified when [ 125 I] iodoproxyfan binding was displaced by the agonist imetit. High-affinity binding also occurred at cytochrome P450 enzymes. This binding was not inhibited by HA, H 3 R agonists, or Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
The role of histamine in human mammary carcinogenesis
Cancer Biology & …, 2008
There is increasing evidence that describes a histamine role in normal and cancer cell proliferation. To better understand the importance of histamine in breast cancer development, the expres‑ sion of histamine H3 (H3R) and H4 (H4R) receptors and their ...
Biochemical and Biophysical Research Communications, 1983
We compared the interaction of AH 22216 (a new histamine H2 receptor antagonist) and cimetidine on the receptor-cAMP systems sensitive to histamine and to Vasoactive Intestinal Peptide (VIP) in the human gastric cancer cell line HGT-1. When added simultaneously with histamine (10(-4) M), the potency of AH 22216 is similar to that of cimetidine (IC50 = 4-6.6 X 10(-6) M, respectively). Schild plot analysis indicated a non-competitive inhibition by AH 22216 (pA2 = 6.22, slope = 1.4 +/- 0.03). Preincubations of AH 22216 (10 min, 10(-5) M) with HGT-1 cells (even after a washout period) resulted in a complete and persistent (60 min) inactivation of the subsequent histamine effect, without changing the kinetics of the VIP-induced stimulation in the system. Under these conditions, the potency of AH 22216 increased from 6.6 to 0.7 X 10(-6) M. This inactivation was not observed with cimetidine. The data indicate that AH 22216 is an irreversible and specific inhibitor of the gastric histamine H2 receptor.
Histamine receptors and cancer pharmacology: an update
British Journal of Pharmacology, 2018
In the present review we will discuss the recent advances in the understanding of the role of histamine and histamine receptors in cancer biology. The controversial role of the histaminergic system in different neoplasias including gastric, colorectal, oesophageal, oral, pancreatic, liver, lung, skin, blood and breast cancers will be reviewed. The expression of