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

Abstract：

BACKGROUND AND PURPOSE: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. EXPERIMENTAL APPROACH:Xenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H₄R agonists were employed: histamine (5 mg kg⁻¹), clozapine (1 mg kg⁻¹) and the experimental compound JNJ28610244 (10 mg kg⁻¹). RESULTS:Data indicate that developed tumours were highly undifferentiated, expressed H₄R 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 H₄R agonist groups (13.1 ± 1.2, P < 0.01 in histamine group; 15.1 ± 1.1, P < 0.001 in clozapine group; 10.8 ± 0.7, P < 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, P = 0.0025; Gehan-Breslow-Wilcoxon Test, P = 0.0158) and tumoural apoptosis. CONCLUSIONS AND IMPLICATIONS:Histamine through the H₄R exhibits a crucial role in tumour progression. Therefore, H₄R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Martinel Lamas DJ,Croci M,Carabajal E,Crescenti EJ,Sambuco L,Massari NA,Bergoc RM,Rivera ES,Medina VA

doi

10.1111/bph.12137

subject

Has Abstract

pub_date

2013-09-01 00:00:00

pages

188-99

issue

eissn

0007-1188

issn

1476-5381

journal_volume

170

pub_type

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