Efeito anticâncer de derivados sintéticos da cumarina

Abstract

Cancer is a set of diseases that are characterized by uncontrolled proliferation of malignant cells with the ability to invade adjacent tissues and organs. This public health problem is worldwide and is among the top six causes of death. Among the more than one hundred types, lung cancer is the most incident and deadliest among men and women in the world. Despite the advancement of medicinal chemistry, the high mortality rates related to lung cancer are due to the lack of specific treatments and the ineffective responses of chemotherapeutic drugs used to treat this disease. Knowing that the epithelial-mesenchymal transition (EMT) gives cells migratory and invasive properties and that cell migration depends on this process to happen, the discovery of a substance that acts by inhibiting EMT in tumor cells becomes na interesting target for research and development of a new drug with more effective antitumor properties. In this sense, the general objective of this work was to evaluate the anticâncer activity of coumarin syntactic derivatives in tumor lines and to identify their potential action in the modulation of EMT in vitro. For the analysis of cell viability, MTT assays (3- [4,5- dimethyl-thiazol-2-yl] -2,5-diphenyltetrazolium bromide) were performed on two tumor cell lines: A549 (human pulmonary adenocarcinoma) and H2170 (human lung carcinoma), treated with synthetic coumarin derivatives for 24h, at a concentration of 12 μM and chemotherapy control cisplatin (132,84 μM). To assess the interference of derivatives in EMT and cell migration, the EMT induction assay and, finally, the horizontal migration assay, both in A549 cells treated with derivatives 106, 123A and 123B at 12 μM, stimulated or not with IL-1β for 24 hours. Treatment with derivatives 106 and 123B significantly reduced the viability rate in A549 and H2170 cells. Derivative 123A reduced the viability rate, only, in A549 cells. Only treatment with derivative 106 was able to attenuate the morphological changes, related to EMT (epithelium-mesenchymal transition), in A549 cells stimulated by IL-1β. But all three derivatives were able to reduce the rate of cell migration, induced by IL-1β in A549 cells. The results obtained suggest that derivatives 106, 123A and 123B have an anti-tumor effect through different mechanisms and are independent of morphological changes for a mesenchymal phenotype. Knowing that proliferation, migration and EMT are crucial for the development of cancer and tumor metastasis and that derivative 106 significantly interfered with these three processes in A549 cells, derivative 106 proved to be an interesting target for further study in the search for a more effective antitumor substance for lung cancer.