Active principles obtained from plants of Argentina as new therapeutic tools against multi-drug resistant tumors

JORAY M.B.; KIKELJ D.; LAIOLO J.; TOMASIC T.; CARPINELLA M. C.; GARCIA MANZANO M.F.; VERA D.M.A.

Jornada; CA17104 -STRATAGEM- NEW DIAGNOSTIC AND THERAPEUTIC TOOLS AGAINST MULTIDRUG RESISTANT WG3 Online Meeting; 2020

Chemotherapy is one of the most powerful tools for successful treatment of cancer; however, this approach is often challenged by the development of multidrug resistance (MDR). The resistant phenotype represents an adaptive response of tumor cells, mediated via a range of cellular modifications, such as altered metabolism of drugs and changes in targets that result in less effective anticancer agents. Another major mechanism that leads to resistance is the presence of membrane transporters that extrude a broad range of drugs from cancer cells, thereby preventing to fulfill their cytotoxic activity. P-glycoprotein (P-gp) is probably the best known among these. Despite it constitutes the most important cause of failure in therapies, there are no P-gp inhibitors suitable for chemotherapies so far. Under this scenario, the search for agents able to hit resistant cancer cells and overcome P-gp-mediated MDR is a high priority. Since antiquity, plant products have been an invaluable source of leading molecules for drug development with a significant contribution to the treatment of cancer. As part of our continuous search for agents with anticancer properties, a panel of more than 160 extracts obtained from plants of Argentina and of bioactive metabolites isolated from these, were analyzed in order to determine their ability to inhibit the development of cancer cells resistant to conventional cytotoxic agents and their potential to reverse MDR in cells with over-expression of P-gp. New and known compounds, in particular sesquiterpene lactones, showed to be highly effective against MDR cancer cells. The antiproliferative effect was mediated by cell cycle arrest followed by apoptosis. Other metabolites, among them a triterpene and a lignan, and synthetic derivatives thereof designed using computer-assisted techniques, showed to inhibit the efflux of chemotherapeutic drugs from leukemia cells overexpressing P-gp, resulting in an increased sensitization to these. Molecular modeling studies showed that subject compounds mainly bind to the P-gp at transmembrane helices (TMH) 4, 5, and 6.