Avaliação do efeito antitumoral da frutose-1,6-bisfosfato e do metoxieugenol em adenocarcinoma de endométrio humano in vitro

Abstract

Endometrial cancer is considered the sixth most commonly diagnosed cancer in the female population. Although surgical removal is the treatment of choice for most patients, about 15 to 20% have recurrences after surgery. Radiotherapy and/or chemotherapy adjuvant to surgical treatment may be recommended based on pathological criteria. However, it is estimated that these treatments benefit only 10 to 15% of patients. In the case of preserving fertility or metastatic and/or recurrent disease, hormone therapy is an alternative treatment. Considering the restricted therapeutic options, high rates of tumor resistance, and recurrence, the search for new antitumor drugs is necessary. The present study aimed to evaluate the antitumoral effect of fructose-1,6-bisphosphate (F1,6BP) and methoxyeugenol (MET) in a human cell line of endometrial adenocarcinoma cancer (Ishikawa). Both molecules tested showed antiproliferative and non-cytotoxic effects in endometrial cancer cells, followed by increased levels of reactive oxygen species, mitochondrial dysfunction with increased mitochondrial membrane potential, and reduced cell proliferative capacity even after treatment withdrawal. However, the chemotherapeutic mechanisms induced by the treatments were different: while F1,6BP was responsible for the induction of programmed cell death by apoptosis with increased gene expression of pro-apoptotic regulators p53 and Bax, treatment with MET led to an increase in the nuclear area and cell lysosomal content which, together with the increase in p53/p21 gene expression and decrease in CDK4/6 gene expression, corroborate the triggering of an antiproliferative effect by cellular senescence. The results demonstrate that the molecules under study can act as potential antitumor agents against endometrial cancer. In non-tumoral renal cells (Vero), the treatments with F1,6BP and MET showed non-cytotoxic effects and potentially increased the tolerance of these cells against cisplatin-induced toxicity.