Lorena Sambuco

Histamine regulates pancreatic carcinoma cell growth through H3 and H4 receptors

Several lines of evidence suggest that histamine (HA) may act as an autocrine or paracrine growth factor increasing proliferation rate in normal and malignant tissues. Previously we reported that histamine H1 and H2 receptors are expressed and associated with cell growth in Panc-1, a cell line derived from a human ductal pancreatic carcinoma [1]. This work was to evaluate the presence of histamine H3 and H4 receptors and their potential involvement in PANC-1 cells proliferation.

Role of H4 receptor in histamine-mediated responses in human melanoma.

We have previously reported that histamine at micromolar concentrations reduces the proliferation of melanoma cell lines. It is also known that melanoma cells express histamine H1, H2, and H3 receptors. The aim of this study was to investigate the presence of histamine H4 receptor (H4R) in human melanoma cells and its associated biological processes. To better understand the importance of histamine in tumor development, we explored the expression of H4R in human melanoma tissue biopsies. The expression of H4R in WM35 and M1/15 cells was analyzed by reverse-transcription–PCR, western blot, and immunocytochemistry. To characterize the biological responses we evaluated cell proliferation by clonogenic assay and 5-bromo-2′-deoxyuridine incorporation. In addition, cell senescence and differentiation were determined by &bgr;-galactosidase enzyme assay and dopa oxidase activity, respectively. The expression levels of H4R were determined by immunohistochemistry in 19 samples of human malignant lesions. Results indicate that melanoma cells express H4R at the messenger RNA and protein levels. By using histamine agonists, antagonists, and H4R small-interfering RNA we showed that the inhibitory effect of histamine on proliferation was in part mediated through the stimulation of the H4R. The decrease in proliferation was associated with an induction of cell senescence and an increase in melanogenesis, which is a differentiation marker of these cells. Furthermore, H4R was expressed in 42% of human melanoma biopsies. To our knowledge, this is the first report that describes the presence of the H4R in melanoma cells and tissue, suggesting a potential therapeutic application of H4R ligands.

Therapeutic potential of histamine H4 receptor agonists in triple‐negative human breast cancer experimental model

The presence of the histamine H4 receptor (H4R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H4R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model.

Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma

BACKGROUND Functional presence of histamine H4 receptor (H4R) was demonstrated in human melanoma cell lines and biopsies. OBJECTIVE The purposes of this work were to investigate signal transduction pathways and biological responses triggered by the activation of H4R in human primary (WM35) and metastatic (M1/15) melanoma cell lines and to evaluate the in vivo antitumor activity of histamine (HA) and clozapine (CLZ) on human M1/15 melanoma xenografts. METHODS Clonogenic assay, incorporation of BrdU, cell cycle distribution, phosphorylation levels of ERK1/2 and cAMP production were evaluated in vitro. An experimental human melanoma model was developed into athymic nude mice. Tumor growth, survival and histochemical studies were performed in order to investigate the expression levels of H4R, HA, PCNA, mitotic index (MI), and angiogenesis. RESULTS The results indicate that H4R agonists inhibited forskolin-induced cAMP levels only in M1/15 cells while increased phosphorylation levels of ERK1/2 and decreased proliferation in both cell types. In vivo studies show that HA and CLZ (1mgkg(-1), sc) significantly increased median survival and decreased tumor volume. These effects were associated to a reduction in MI, in the expression of proliferation marker and in intratumoral neovascularization. CONCLUSIONS We conclude that HA and CLZ exhibit an antitumoral effect in vitro and in vivo on human melanoma, suggesting the therapeutic potential of these compounds for the treatment of malignant melanoma.

Effect of histamine on the expression of metalloproteinases and cell adhesion in breast cancer cell lines

Changes in cell adhesion and matrix metalloproteinases production (MMPs) are pivotal for tumor progression to occur. The MMPs that degrade extracellular matrix, MMP-2 and MMP-9, are associated with the invasive potential of cancer cells. Tissue inhibitors of metalloproteinases (TIMPs), small molecules which form high affinity complexes with active MMPs, regulate their proteolytic activity. E-Cadherin, a cell-cell adhesion molecule, plays an important role in the separation of cells from original tumors and may also regulate MMP-2 enzymatic activity [1]. Histamine (HA) has been demonstrated to be a well-established growth factor in several human and experimental neoplasms. We have recently reported that HA modulates cell survival and invasiveness in the human pancreatic adenocarcinoma cell line, PANC-1 [2]. Our aim was to study the effect of HA on cell adhesion and expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 in human tumorigenic and non-tumorigenic mammary cell lines, MDA-MB-231 and HBL-100, respectively.

Histamine therapeutic efficacy in metastatic melanoma: Role of histamine H 4 receptor agonists and opportunity for combination with radiation

The aims of the work were to improve our knowledge of the role of H4R in melanoma proliferation and assess in vivo the therapeutic efficacy of histamine, clozapine and JNJ28610244, an H4R agonist, in a preclinical metastatic model of melanoma. Additionally, we aimed to investigate the combinatorial effect of histamine and gamma radiation on the radiobiological response of melanoma cells.Results indicate that 1205Lu metastatic melanoma cells express H4R and that histamine inhibits proliferation, in part through the stimulation of the H4R, and induces cell senescence and melanogenesis. Daily treatment with H4R agonists (1 mg/kg, sc) exhibited a significant in vivo antitumor effect and importantly, compounds reduced metastatic potential, particularly in the group treated with JNJ28610244, the H4R agonist with higher specificity. H4R is expressed in benign and malignant lesions of melanocytic lineage, highlighting the potential clinical use of histamine and H4R agonists. In addition, histamine increased radiosensitivity of melanoma cells in vitro and in vivo. We conclude that stimulation of H4R by specific ligands may represent a novel therapeutic strategy in those tumors that express this receptor. Furthermore, through increasing radiation-induced response, histamine could improve cancer radiotherapy for the treatment of melanoma.