Clozapine, a new therapeutic approach for breast cancer?

DIEGO MARTINEL LAMAS; GRACIELA CREMASCHI; MELISA NICOUD; JUAN CARLOS PERAZZO; HELENA STERLE; VANINA MEDINA

Mar del Plata

Congreso; LXI Reunión Anual de la SAIC, Sociedad Argentina de Investigación Clínica; 2016

Previous data provide evidence supporting the anticancer effects of antipsychotics that could partially explain the lower incidence of cancer in patients with schizophrenia compared with the general population. We have previously demonstrated that clozapine inhibited proliferation of human breast cancer and melanoma cells. The aim of this work was to investigate the in vitro and in vivo antitumor activity of clozapine in 4T1 triple negative breast cancer (TNBC) model. For that purpose, the effect of clozapine on processes associated with cell death and survival, metabolism of ROS and DNA damage was studied in murine 4T1 breast cancer cells. Clozapine effects on tumor progression was further investigated in syngeneic mice, inoculated orthotopically with 4T1 murine TNBC cells.Results indicate that clozapine inhibited clonogenic proliferation and produced a 2-fold decrease in BrdU incorporation of 4T1 cells (P˂0.01). This effect was associated with an increase in the differentiation marker Nile red evaluated by flow cytometry. Accordingly, in vivo treatment of 4T1 tumors with clozapine (1 mg/kg.day) reduced tumor weight (1.3±0.1 vs. 2.1±0.3 g, P˂0.05) and volume (1.3±0.1 g vs. 1.9±0.3 cm3, P˂0.05). Histopathological studies demonstrate that tumors of the clozapine-treated group were microscopically homogeneous with extended areas of differentiation (e.g. glands).We conclude that clozapine produces antitumoral effects in vitro and in mouse syngeneic model of TNBC, suggesting that it could be a potential therapeutic agent in the treatment of breast cancer.