Efeito antitumoral do triterpeno pentacíclico friedelina no modelo murino de carcinoma de Ehrlich ascítico

Abstract

Friedelin (FD) is a secondary metabolite present in different plant species with important pharmacological activities described, which include anti-inflammatory, antioxidant, antidiabetic, and neuroprotective actions. Recently, it was reported that FD has cytotoxic and apoptotic effects in vitro on human breast adenocarcinoma and human leukemia cells, illustrating its promise as a potential candidate for drug development in the treatment of cancer. Thus, the objective of this work was to investigate the antitumor activity of FD against the murine model of Ehrlich ascitic tumor (tEa). After standardizing the tEa model at UFAL, Swiss female mice induced with tEa were distributed into 5 groups (Tumor control, 5-Fluorouracil 200 μmol/Kg, 2% Ethanol, and FD in two doses, 50 and 200 μmol/Kg) and treated by 5 consecutive days. On days 1, 6, and 11, the animals' abdominal circumference weight was recorded and photographic and X-ray images were captured. After the last treatment, the animals were euthanized for collection and quantification of tumor fluid, cellularity, morphological analysis of tumor cells, analysis of oxidative and inflammatory stress mediators, cell death, angiogenesis, and analysis of gene expression by RT-qPCR of enzymes antioxidants and proteins involved in cell apoptosis. The influence of the age of the animals and the time of tumorigenesis on tumor development and progression in the tEa model was observed, allowing the design of an experimental protocol for the pharmacological analysis of substances with potential antitumor effects. FD showed a cytotoxic profile in the primary culture of tEa cells and significantly reduced all parameters of tumor development evaluated in this work, with a reduction in total, tumor, and leukocyte cellularity, and a decrease in the infiltrate of neutrophils and macrophages, with an index of inhibition of tumor development similar to the drug used as a control at a dose 4 times lower than that of the chemotherapy widely used in clinical practice. FD attenuated the levels of ROS and increased the gene expression of the antioxidant enzymes superoxide dismutase and catalase. Furthermore, FD induced cellular apoptosis by modulating markers involved in the apoptosis signaling cascade and reduced tumor angiogenesis by suppressing endothelial growth factor secretion by tumor cells. The antiproliferative activity of FD in the tEa model culminated in the increase in survival time and life expectancy of mice carrying tEa. It can be concluded that FD is shown to be a molecule with antitumor potential, being able to modulate the tumor microenvironment and promote cell apoptosis, inhibiting tumor progression in the tEa model.