Estudo in vitro da eficácia antineoplásica de metformina e de everolimus em monoterapia e terapia combinada com antineoplásicos convencionais no tratamento do câncer de ovário

Abstract

Ovarian cancer (CAOV) is the most lethal of the gynecologic malignancies, partially due to the lack of specific signs and symptoms as well as diagnosis strategies insufficient. Most women affected by CAOV are diagnosed in advanced stages of the disease, and despite the initial satisfactory response to antineoplastic drugs, eventually develop chemoresistance and recurrence. Therefore, new therapeutic agents which focus on molecular targets has emerged as the prospect of better prognosis CAOV. In this context, we investigated the action of metformin and everolimus, modulators of protein kinase Mammalian Target of Rapamycin (mTOR) in the CAOV cell lines ES-2 and A2780. Metabolic cell viability (VCM) was reduced by metformin and everolimus in different concentrations, in addition intensifying the effect of paclitaxel. Combining metformin 10µM with taxane 100nM the VCM was reduced in 56,55% in the cell line ES-2, and 71,38% in A2780 compared to control. Similarly, everolimus 0,06 nM added to paclitaxel 100 nM decreased VCM in 66,4% and 73,38% in the cell lines ES-2 and A2780, respectively. Moreover the maintenance of metformin dose (10µm) and everolimus (0,06nM) associated whith paclitaxel 12,5nM promoted a VCM compatible to taxane 100nM. We performed anexinaV/PI assay in ES-2 lineage, and a low percentage of apoptotic/necrotic cells was induced (metformin 10µM, 4.35%/3.85%; everolimus 0,06nM, 1.25%/5.1 %), however, we found its action on VCM and thus suggest occurrence of additional processes, such autophagic cell death. In addition, the cells predominated in phase GO/G1 with metformin and everolimus treatment, and there was an increase of cells in G2/M and sub-G0 phase with metformin and everolimus treatment, respectively. Our findings highlight the potential application of metformin and everolimus in the treatment of CAOV, a major challenge of clinical oncology