Therapeutic potential of H4R agonists in an experimental model of human breast cancer

D MARTINEL LAMAS; M CROCI; L SAMBUCO; E CARABAJAL; N MASSARI; RM BERGOC; ES RIVERA; VA MEDINA

Belfast

Congreso; European Histamine Research Society, XLI Annual Meeting; 2012

We have previously reported the presence of the histamine H4 receptor (H4R) in benign and malignant lesions and cell lines derived from the human mammary gland. The H4R is one of the main subtypes responsible for the histamine-induced responses in MDA-MB-231 breast cancer cells. The aim of the present work was to evaluate the effects of H4R ligands on the survival, tumour growth rate, metastatic capacity and molecular pattern of expression of antigens related with the proliferative and apoptotic potential in a breast cancer experimental model. For that purpose, we established xenografted tumours of the highly invasive human breast cancer cell line MDA-MB-231 in immune deficient nude mice. We employed the following H4R agonists: histamine (1 and 5 mg/Kg, sc), clozapine (1 mg/Kg, sc), and the experimental compound JNJ28610244 (10 mg/Kg, sc). Results indicate that developed tumours were highly undifferentiated and that the H4R was the major histamine receptor expressed. They also exhibited high levels of histidine decarboxylase, histamine content and proliferation marker (PCNA) while displaying low levels of apoptosis. Mice of the untreated group displayed a median survival of 60 days, and a tumour doubling time exponential growth of 7.4±0.6 days. A significant decrease in tumour growth evidenced by an augmentation of the tumour doubling time was observed in H4R agonist groups (13.1±1.2, P