Histamine

[Rich66]

Volume 58, Issue 6, Pages 867-870 (June 2009) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1939825/ PDF http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1939825/

Histamine
A Potential Therapeutic Agent for Breast Cancer Treatment?
Farhad Vesuna and Venu Raman*
Department of Radiology; Johns Hopkins University-School of Medicine; Baltimore Maryland USA
*Correspondence to: Venu Raman; Department of Radiology; Johns Hopkins University-School of Medicine; 720 Rutland Avenue; 340 Traylor Bldg.; Baltimore Maryland 21205 USA; Tel.: 410.955.7492; Email: vraman2@jhmi.edu


The finding that histamine receptor expression is observed in breast cancer cell lines warrants further investigation into the use of histamine antagonists to suppress cell growth and proliferation. There is evidence in the literature to indicate that an estrogen antagonist, tamoxifen (TAM), can bind to histamine-like receptors and reduce proliferation.14 Thus, it may be possible to generate specific histamine receptor antagonists to treat breast cancer. What is known is that some of the antagonists against the H1 and H2 receptors lack the specificity or potency to completely downregulate downstream signaling pathways to produce any discernible effect on breast cancers.15 Till date, the current research in this field has not advanced enough to come to any definite conclusion.

In this issue, Medina, et al.16 report the expression of all four histamine receptors in the normal breast cell line, HBL-100 and in an aggressive breast cancer cell line, MDA-MB-231. The aim of the study was the identification of biological responses that are regulated by histamine in malignant breast cells. Although H3 and H4 receptors were shown to be restrictive in their expression pattern (brain and the hematopoietic system respectively), their results indicate the pleiotropism and potentially novel functions of histamine receptors in breast epithelia. Besides receptor expression, the authors’ also detected higher levels of histamine in MDA-MB-231 cells as compared to the HBL-100 cell line. Addition of histamine to these cells caused a biphasic effect on proliferation, differentiation and apoptosis. The use of 10 μM histamine reduced proliferation, while increasing differentiation and apoptosis in MDA-MB-231 cells but not in HBL-100 cells. The inverse was true when 10 nM of histamine was added. These results bring into question the physiological role of high intracellular histamine levels in aggressive breast cancer cell lines as compared to normal cells. Furthermore, the differential effects of extracellular histamine on cancer cells and normal cells are perplexing. If histamine levels are already high in aggressive breast cancer cell lines and the autocrine and paracrine systems are functional, then one would anticipate an inhibition of growth and increased propensity towards cell death. Thus, it may be that these cancer cells have either adapted to the high levels of intracellular histamine or have altered some biological pathways to decrease the signaling effects of endogenous histamine. Furthermore as the level of exogenous histamine added far exceeds the concentration of histamine released to the extracellular medium, it may trigger alternative signaling pathways that indirectly affect cellular growth and proliferation. The authors go on to show that the modulation observed in proliferation of the malignant cell line was mediated via the H3 and not the H2 receptor. This could be one possible explanation as to why the use of a H2 receptor antagonist in breast cancer clinical trials has been unsuccessful thus far.15

Another aim of the study was to examine the role of histamine in cellular responses to radiation and concomitant reactive oxygen species (ROS) production in cells. ROS have been shown to contribute to carcinogenesis by increasing mutagenesis, inhibiting differentiation and inactivating tumor suppressors and activating oncogenes.17-20 As is the case with many chemical carcinogens, small amounts of ROS can act as mitogens but higher doses can lead to cell death. High levels of oxidative stress result in loss of mitochondrial transmembrane potential, release of cytochrome-c into the cytoplasm and degradation of mitochondrial DNA eventually leading to apoptosis. The authors have shown that histamine can increase intracellular ROS namely superoxide and hydrogen peroxide and decrease catalase activity in breast cancer cells. In addition, the authors show that histamine can augment radio-sensitization in malignant breast cancer cells. Both these results of histamine augmenting hydrogen peroxide levels and radio-sensitizing malignant breast cancer cells selectively are important findings that need to be investigated further.

Medina, et al.’s approach of using breast cancer cell lines is a step towards validating the anti-proliferative and apoptotic functions of histamine. Additional studies aimed at deciphering the mechanisms by which histamine exerts its effects on breast epithelium have to be performed which would give a more complete understanding of histamine function at the cellular level. In addition, subsequent confirmation of these findings will necessitate using multiple breast cancer cell lines and normal breast cells as well as the use of animal models. Such studies could determine the efficacy of histamine in controlling breast cancer growth both in xenograft and in spontaneous breast cancer models, and thus further explore the use of histamine as a therapeutic agent for the treatment of breast cancer. In addition, the side effects of histamine, especially its role in autoimmune disease must be part of such studies. In conclusion, the data presented by Medina, et al. in this paper provides some evidence of a possible use of histamine to control growth and proliferation of breast cancer cells. The finding that histamine receptors are expressed in breast cancer cells and that histamine can function as a growth inhibitor may point towards a novel approach to treat breast cancer.


http://www.metabolismjournal.com/art...076-6/abstract
Metabolism of histamine in tissues of primary ductal breast cancer

Jarosław von Mach-Szczypiński, Stanisław StanoszCorresponding Author Informationemail address, Krzysztof Sieja, Małgorzata Stanosz

Received 27 May 2008; accepted 5 February 2009. published online 17 April 2009.
Abstract

Histamine performs an important role in the pathologic and physiologic aspects of the breast gland. Among monoamines, histamine demonstrates the greatest proliferative activity in breast cancer. The aim of the study was to evaluate histamine concentration in plasma and tissues of breast cancer dependent on the activity of histamine metabolism enzymes in neoplasmatic tissues of the breast gland. Ninety-five women aged 38 to 70 years were divided into 2 groups. The control group (group I) consisted of 30 healthy women. Group II consisted of 65 women with primary ductal breast cancer. The concentration of histamine in plasma was assessed by immunoenzymatic method. The concentration of histamine in cancerous tissues of the breast and the metabolism of histamine enzymes, specially histidine decarboxylase, decarboxylase of aromatic l-amino acids, N-histamine methyltransferase, monoamine oxydase B, and diamine oxydase, were determined using isotope technique. In the course of 24 hours, excretion of N-methylimidazoleacetic acid was evaluated by the methods of chromatography. The statistical analysis was made based on Statistica Pl Ed (StatSoft, Cracow, Poland, 1998). A significant increase in the concentration of histamine in plasma (P < .01) and tissues of ductal breast cancers (P < .001), and in the activity of histidine decarboxylase (P < .01), aromatic l-amino acids (P < .05), and histamine methyltransferase (P < .05) was found. Activity of monoamine oxidase B (P < .01) and diamine oxidase (P < 0.01) and excretion of N-methylimidazoleacetic acid were significantly decreased compared with the control group (P < 0.001). The conclusions are as follows: (1) Concentration of histamine in the plasma of women is dependent on the concentration of histamine in the tissues of ductal breast cancers. (2) The significant increase of histamine in cancerous tissues of ductal breast cancer could suggest the participation of this monoamine in the development of breast cancer. (3) The increase of histamine concentrations in ductal breast cancer tissues can be connected with the disturbances of the balance between synthesis and enzymatic inactivation of this monoamine. (4) The concentration of histamine in the plasma of women with ductal breast cancers is dependent on the number of involved lymph nodes and the grade of histologic malignancy.