CLOZAPINE AS A POTENTIAL ANTI-CANCER DRUG

NICOUD, MB; STERLE HA; MASSARI NA; TÁQUEZ DELGADO, MA; MARTINEL LAMAS DJ; HERRERO DUCLOUX, MA; CREMASCHI GA; MEDINA VA

Buenos Aires

Congreso; Reunión conjunta de Biociencias; 2017

We have previously demonstrated that clozapine, a well-known antipsychotic inhibited proliferation of human breast cancer and melanoma cells. The aim of this work was to investigate the effect of clozapine alone or in combination with a widely used chemotherapeutic agent (doxorubicin, Dox), on an immunocompetent triple negative breast cancer (TNBC) model. For that purpose, proliferation and apoptotic assays and DNA damage markers were studied in murine 4T1 TNBC cells. In vivo studies were performed in syngeneic mice, inoculated orthotopically with 4T1 murine TNBC cells. Results indicate that clozapine reduced proliferation in a concentration dependent manner. At 10 µM concentration it produced a 2.5-fold decrease in clonogenic proliferation and in BrdU incorporation of 4T1 cells (P˂0.01). This effect was associated with an induction of apoptosis, evidenced by an increased Annexin-V staining, an increase in the differentiation marker Nile red, and enhanced ROS levels, all assays evaluated by flow cytometry. Accordingly, in vivo treatment of 4T1 tumors with clozapine (1 mg/kg.day, sc) reduced tumor weight (1.3±0.1 vs. 2.1±0.3 g, P˂0.05). Histopathological analysis indicate that clozapine-treated tumors show extended areas of differentiation and reduced mitotic index. Combined treatment of clozapine and doxorubicin was more effective in reducing growth in vitro and in vivo than single treatments. Clozapine potentiated doxorubicin-induced apoptosis and proliferation reduction (P