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 AbbreviationsDym, mitochondrial transmembrane potential; H1R, histamine H1 receptor; H2R, histamine H2 receptor; H3R, histamine H3 receptor; H4R, histamine H4 receptor; HDC, L-histidine decarboxylase; MAPK, mitogen-activated protein kinase; TUNEL, TdT-mediated UTP-biotin Nick End labelling IntroductionCancer continues to be a major health problem for those in developed countries being a leading cause of death worldwide and accounting for 7.9 million deaths in 2007. That number is slated to increase to 11.5 million by the year 2030. Lung, stomach, liver, colon and breast cancer cause the most cancer deaths each year (Parkin et al., 2005;Mathers and Loncar, 2006).A large body of literature indicates that tumorigenesis in humans is a multistep process and that these steps reflect genetic and epigenetic alterations that drive the progressive transformation of normal cells into highly malignant derivatives. More than 100 distinct types of cancer have been described and subtypes of tumours can be found within specific organs representing added challenges to cancer treatments (Hanahan and Weinberg, 2000;Frank and Knowles, 2005;Hall and Giaccia, 2006). Surgery and radiation therapy are by far the most widely used local treatments for cancer and remain mainstays of the effective treatment of cancer to remove the primary tumour or by combining these treatments with chemotherapy, a systemic drug therapy, which are aimed to eradicate micrometastatic disease. The term chemotherapy, in its broadest definition, covers any therapeutic intervention utilizing chemicals and includes the use of any pharmaceutical compounds. In this fashion, BJPBritish Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2010 (Camidge and Jodrell, 2005;Fentiman, 2005). Anticancer drug discovery, development and administration are changing in the post-genomics era. Advances in the understanding of cancer biology and the mo...

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

This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. were identified in L. muta and L. stenophrys venoms. In addition, both venoms contained a large number of bradykinin-potentiating peptides (BPP) and a C-type natriuretic peptide (C-NP). BPPs and C-NP comprised around 15% of the total venom proteins. In both species, the most abundant proteins were Zn 2+ -metalloproteinases (32-38%) and serine proteinases (25-31%), followed by PLA 2 s (9-12%), galactose-specific C-type lectin (4-8%), L-amino acid oxidase (LAO, 3-5%), CRISP (1.8%; found in L. muta but not in L. stenophrys), and NGF (0.6%).On the other hand, only six L. muta venom-secreted proteins matched any of the previously reported 11 partial or full-length venom gland transcripts, and venom proteome and transcriptome depart in their relative abundances of different toxin families. As expected from their close phylogenetic relationship, the venoms of L. muta and L. stenophrys share (or contain highly similar) proteins, in particular BPPs, serine proteinases, a galactose-specific C-type lectin, and LAO. However, they dramatically depart in their respective PLA 2 complement. Intraspecific quantitative and qualitative differences in the expression of PLA 2 molecules were found when the venoms of five L. muta specimens (3 from Bolivia and 2 from Peru) and the venom of the same species purchased from Sigma were compared.These observations indicate that these class of toxins represents a rapidly-evolving Author's personal copy gene family, and suggests that functional differences due to structural changes in PLA 2 s molecules among these snakes may have been a hallmark during speciation and adaptation of diverging snake populations to new ecological niches, or competition for resources in existing ones. Our data may contribute to a deeper understanding of the biology and ecology of these snakes, and may also serve as a starting point for studying structure-function correlations of individual toxins.

Histamine is a biogenic amine responsible for multiple biological actions including regulation of physiological functions of mammary gland. It has been postulated that histamine plays a critical role in proliferation of normal and cancer cells. To investigate the biological responses that histamine exerts in malignant cells derived from human mammary gland, we evaluated in MDA-MB-231 line the expression of histamine receptors, histamine intracellular content, the capacity of histamine to influence proliferation, cell cycle progression, differentiation and apoptosis. We also studied histamine involvement in cellular response to ionizing radiation. HBL-100 cells were used as control of non-tumorigenic breast cells. Proliferation and surviving fraction were assessed by clonogenic assay. Cell cycle progression and lipid accumulation were determined by flow cytometry while apoptosis was studied by Annexin V and DNA fragmentation assays. Both cell lines expressed the four histamine receptors subtypes as evaluated by western blot and RT-PCR analyses, and present endogenous histamine. Histamine regulated proliferation of cancer cells in a dose-dependent way and 10 microM histamine reduced significantly proliferation to 23% inducing cell cycle arrest in G(2)/M phase, differentiation by 26% and a significant increase in the number of apoptotic cells (p < 0.01). These responses were not observed in HBL-100 cells. Furthermore, 10 microM histamine exclusively enhanced the radiosensitivity of MDA-MB-231 cells. These results represent the first report about the expression of H3 and H4 receptors in human breast cells. In addition, we conclude that histamine exerts different effects on biological responses of normal and cancer breast cells representing a promising target for the development of more specific and less toxic cancer therapies.

No abstract