Papel de um derivado semissintético do [6]-gingerol (SSi6) na morte celular e efeitos antimetastáticos no câncer de mama triplo negativo: estudos in vitro e in vivo

Abstract

Nowadays, the development of new drugs/compounds to combat breast cancer is one of the main challenges of this research area. Among the different subtypes of this disease, triple negative breast cancer (TNBC) is considered the most aggressive and the one with the worst prognosis, since it has no specific therapeutic target. In this regard, the development of potential antitumor drug candidates for the treatment of this subtype is a major clinical and research challenge. Thus, in the first chapter of this thesis, the in vitro selective cytotoxic effect of SSi6 on the triple negative breast cell line MDA-MB-231 was shown. Unlike its natural homologue [6]-gingerol (6G), this new compound induced cell death by activation of two processes, autophagy (initial activation upon treatment) and caspase-independent apoptosis (late induction upon treatment), promoted by the generation of reactive oxygen species. This strategy of inducing combined mechanisms of cell death, is an interesting alternative for the treatment of triple negative tumors resistant to drugs that induce canonical apoptosis. Given this promising activity, in the second chapter the antitumor and antimetastatic effects of SSi6 on MDA-MB-231 cells in xenograft models were investigated. First, it was demonstrated that SSi6 does not cause toxic effects in vivo, shown mainly by monitoring the body weight of mice and by hematological and histological parameters. In the orthotopic xenograft model, SSi6 (15 mg/kg) slowed down the growth of the primary tumor, as well as the metastatic progression from axillary lymph nodes to the lungs. Finally, in the second xenograft model with resection of the primary tumor, the SSi6 was confirmed to block the progression of metastases from axillary lymph nodes to the lungs and other visceral organs. Taken together, the results demonstrate that SSi6 is a promising compound to be investigated in other preclinical models, which would allow its future application in clinical trials as a single or complementary therapy for the treatment of TNBC.