Avaliação da atividade antitumoral e da atividade protetora do cloridrato de epiisopiloturina nos efeitos colaterais do 5- fluorouracil em um modelo de carcinoma colorretal murino (Ct26.Wt)

Abstract

Cancer is one of the main causes of morbidity and mortality in the world. Among the available therapies, chemotherapy drugs have low specificity, causing damage to healthy tissues and causing undesirable side effects. In order to deal with this problem, new therapeutic regimens are essential. In this sense, Epiisopiloturine Hydrochloride in its saline form (EPI-HCL), an alkaloid extracted from Pilocarpus microphyllus, was evaluated for its antitumor potential and reduction of colonic toxicity caused by 5-Fluorouracil (5-FU) in vitro and in alive. To evaluate interference with the chemotherapeutic effect in vivo, female BALB/c mice, inoculated with CT26.WT lineage cells, were treated intraperitoneally for 10 days with 5-FU 20mg/kg every other day, EPI-HCL at concentrations of 25 and 50mg/kg/day and with the combination of 5-FU 20mg/kg/2day + EPI-HCL 50mg/kg/day. EPI-HCL did not show cytotoxicity or synergism with 5-FU against colorectal cancer lines CT26.WT and HCT-116 in the MTT assay. In the in vivo study, the alkaloid did not cause isolated tumor inhibition and did not influence the percentage of inhibition of the chemotherapy agent. Macroscopic analysis of the organs revealed that the associated treatment was able to prevent the reduction in liver and spleen weight induced by 5-FU, in addition to the increase in colon weight and the colonic weight/length ratio, which suggests the presence of edema. Animals in the 5-FU group showed an increase in the depth of intestinal crypts in the colon, which was avoided with the joint administration of EPI-HCL. Furthermore, healthy BALB/c mice, without tumor induction, treated with EPI-HCL 50mg/kg/day, did not show signs of toxicity. Only a reduction in liver weight was observed compared to the healthy saline group. These results highlight the potential of EPI-HCL as part of the therapeutic regimen with 5-FU, as it did not present toxicity and reduced side effects without interfering with the antitumor activity of the chemotherapy drug.