Therapeutic potential of histamine H4 receptor agonists in triple‐negative human breast cancer experimental model. (15th August 2013)

• Record Type: Journal Article
• Authors: Martinel Lamas, Diego J; Croci, Maximo; Carabajal, Eliana; Crescenti, Ernesto J V; Sambuco, Lorena; Massari, Noelia A; Bergoc, Rosa M; Rivera, Elena S; Medina, Vanina A
• Is Part Of: British journal of pharmacology. Volume 170:Number 1(2013:Sep.)
• Page Start: 188
• Page End: 199
• Publication Date: 2013-08-15
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12137
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12137-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>The presence of the histamine H<sub>4</sub> receptor (H<sub>4</sub>R) 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 H<sub>4</sub>R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model.</p> </sec> <sec id="bph12137-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>Xenograft tumours of the highly invasive human breast cancer cell line MDA‐MB‐231 were established in immune deficient nude mice. The following H<sub>4</sub>R agonists were employed: histamine (5 mg kg<sup>−1</sup>), clozapine (1 mg kg<sup>−1</sup>) and the experimental compound JNJ28610244 (10 mg kg<sup>−1</sup>).</p> </sec> <sec id="bph12137-sec-0003" sec-type="section"> <title>Results</title> <p>Data indicate that developed tumours were highly undifferentiated, expressed H<sub>4</sub>R and exhibited high levels of histamine content and proliferation marker (PCNA) while displaying low apoptosis. Mice of the untreated group displayed a median survival of 60 days and a tumour doubling time of 7.4 ± 0.6 days. A significant decrease in tumour growth evidenced by an augment of the tumour doubling time was observed in the H<sub>4</sub>R agonist groups (13.1 ± 1.2, <italic>P</italic> < 0.01 in histamine group; 15.1 ± 1.1, <italic>P</italic> < 0.001 in clozapine group; 10.8 ± 0.7, <italic>P</italic> < 0.01 in JNJ28610244 group). This effect was associated with a decrease in the PCNA expression levels, and also reduced intratumoural vessels in histamine and clozapine treated mice. Histamine significantly increased median survival (78 days; Log rank Mantel‐Cox Test, <italic>P</italic> = 0.0025; Gehan‐Breslow‐Wilcoxon Test, <italic>P</italic> = 0.0158) and tumoural apoptosis.</p> </sec> <sec id="bph12137-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>Histamine through the H<sub>4</sub>R exhibits a crucial role in tumour progression. Therefore, H<sub>4</sub>R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment.</p> </sec> <sec id="bph12137-sec-1001" sec-type="relatedArticles"> <title>Linked Articles</title> <p>This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue‐1</p> </sec> </abstract>