Study of methyl divanylate associated with first-line chemotherapy in triple negative breast cancer cells: evaluation of efficacy, synergism and potential biomarkers

Abstract

Considered quite aggressive and with a worse prognosis, triple negative breast cancer (TNBC) corresponds to about 10 to 24% of breast cancer cases in women, resulting in lower survival and metastases to various organs. In this scenario, enzymes such as matrix metalloproteinases (MMPs) are involved in metastasis, being responsible for cleaving extracellular matrix components, allowing collagen degradation, such as MMP-2 and -9. Transgelins, in turn, are the most recently studied actin-binding proteins, located in the cytoskeleton, and related to carcinogenesis, mainly transgelin-2 (T-2), which always exhibits increased levels in development and progression, especially in metastases, in addition to being related to resistance to chemotherapy. In general, chemotherapy for breast cancer patients consists of anthracyclines, taxanes, ixabepilone, platinum agents, as the only routine systemic treatment. However, this brings many disadvantages to TNBC, mainly in the development of multidrug resistance and formation of secondary tumors. In this regard, the use of phytochemicals such as vanillin and vanillic acid and their esters play a crucial role in modern medicine as an affordable and promising approach. In view of the reports in the literature and previous studies carried out by our research group with vanilloids and their dimers and given that there are no published studies to date, this study aims to evaluate the synergistic effect of methyl divanillate (DMV), dimer of methyl vanillate (MV), with first-choice chemotherapeutic agents in triple negative breast cancer cells (MDA-MB-231 and HCC70) and application in cell culture by three-dimensional magnetic levitation (spheroid formation). Will be evaluated the synergistic effect of DMV with chemotherapy of first choice, doxorubicin (DOX) and paclitaxel (PTX) on cytotoxicity, invasion, production of reactive oxygen species; in addition to the activity of MMP-2, -9, by zymography, and gene expression of MMP-2, -9, TIMP-1, -2, Caspases -3 and -9 and T-2 by qRT-PCR. Additionally, the proteomic profile will be carried out to identify the proteins involved in the oncogenesis of cells exposed to the association of DMV with chemotherapeutics, in addition to the search for new possible biomarkers and the validation of these proteins by western blotting. (AU)