Clozapine as a potential anti-cancer drug.

HELENA STERLE; NOELIA MASSARI; MELISA NICOUD; MONICA TÁQUEZ DELGADO

Capital Federal

Congreso; Reunión Conjunta de Sociedades de Biociencias - LXII Reunión Anual de la SAIC; 2017

Sociedad Argentina de Investigación Clínica

We have previously demonstrated that clozapine, a well-knownantipsychotic inhibited proliferation of human breast cancer and melanomacells. The aim of this work was to investigate the effect of clozapinealone or in combination with a widely used chemotherapeuticagent (doxorubicin, Dox), on an immunocompetent triple negativebreast cancer (TNBC) model. For that purpose, proliferation and apoptoticassays and DNA damage markers were studied in murine4T1 TNBC cells. In vivo studies were performed in syngeneic mice,inoculated orthotopically with 4T1 murine TNBC cells. Results indicatethat clozapine reduced proliferation in a concentration dependentmanner. At 10 μM concentration it produced a 2.5-fold decreasein 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 thedifferentiation marker Nile red, and enhanced ROS levels, all assaysevaluated by flow cytometry. Accordingly, in vivo treatment of4T1 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 indicatethat clozapine-treated tumors show extended areas of differentiationand reduced mitotic index. Combined treatment of clozapine anddoxorubicin was more effective in reducing growth in vitro and invivo than single treatments. Clozapine potentiated doxorubicin-inducedapoptosis and proliferation reduction (P