Histamine H4 receptor agonists are synergistic with doxorubicin in breast cancer.

DIEGO MARTINEL LAMAS; JORGE CORTINA; ELIANA CARABAJAL; JUAN C PERAZZO; ELENA RIVERA; VANINA A MEDINA

Lyon

Congreso; European Histamine Research Society 43rd Annual Meeting; 2014

We have previously demonstrated that the histamine H4 receptor (H4R) is expressed in human breast cancer tissue and cell lines, exhibiting a key role in histamine-mediated biological processes such as cell proliferation, senescence, and apoptosis. The aim of this study was to investigate whether H4R agonists could synergize the effects of chemotherapy in vitro and in vivo in breast cancer models. For that purpose, the effect of doxorubicin (DOX) combined with H4R agonists on processes associated with cell death and survival, metabolism of ROS and DNA damage was studied in human breast cancer cell lines (MDA-MB-231 and MCF-7). The combination therapy of DOX with H4R agonists was further investigated in vivo in human triple negative breast cancer induced in nude mice with MDA-MB-231 cells. Results indicate that DOX inhibited clonogenic proliferation in a concentration dependent manner, and the combined treatment of histamine (HA), clozapine or VUF8430 with DOX (1 nM) significantly synergized the inhibitory effect on proliferation, sensitizing DOX-induced cell death. Also the combination of histamine with DOX enhanced the decrease in the incorporation of BrdU in both cell lines 48 h after treatment [% BrdU positive MDA-MB-231 cells: 50.7±4.2 (control), 40.8±1.3 (DOX), 36.6±1.8 (HA) vs. 30.9±2.7 (DOX+HA), P