EFFECTS OF MYRISTICIN ON THE REVERSAL MECHANISM OF RESISTANCE TO MULTIPLE DRUGS COMMON TO CHEMOTHERAPY

• Grant number: 24/05656-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2024
• End date: July 31, 2025
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Giovanna Barbarini Longato
• Grantee: Felipe Gustavo Carvalho
• Host Institution: Universidade São Francisco (USF). Campus Bragança Paulista. Bragança Paulista , SP, Brazil

Abstract

AbstractThe chemotherapy for cancer treatment faces a barrier that is multidrug resistance (MDR), with no effective response to treatment. There are several mechanisms involved in this resistance, but one of them is the increased expression of some transporter proteins, such as P-glycoprotein (P-gp), which causes the efflux of the chemotherapy drug into the extracellular medium, making treatment difficult. Molecular docking studies recently published by our research group showed that myristicin, a natural compound isolated from nutmeg, is able to bind to P-gp and potentially inhibit its extruder activity, leaving the chemotherapy agent to act on the cell without having the efflux of it. In addition, the compound has been shown to fit important pharmacokinetic parameters, which denote the potential druglikeness of the compound. The present project aims to investigate, in vitro, the effects of myristicin on the mechanism of MDR reversal. To this end, multidrug-resistant NCI/ADR-RES ovarian line cells that overexpress P-gp will be used, which will be treated with myristicin in association with the chemotherapeutics cisplatin and docetaxel, in a three-dimensional cell culture model, which more reliably mimics a tumor, by inducing cell-cell and cell-matrix interactions and allowing the arrangement of cells in layers, conferring a biological barrier to the diffusion of drugs. It is also intended to investigate the mechanism of action of this myristicin-chemotherapeutic association in the processes of programmed cell death, cell cycle and in the mechanism of drug extrusion by P-gp.