Effects of Myristicin in Association with Chemotherapies on the Reversal of the Multidrug Resistance (MDR) Mechanism in Cancer

Abstract

A range of drugs used in cancer treatment comes from natural sources. However, chemotherapy has been facing a major challenge related to multidrug resistance (MDR), a mechanism that results in a decrease in the intracellular concentration of chemotherapeutic agents, resulting in reduced treatment efficacy. The protein most frequently related to this effect is P-glycoprotein (P-gp), which is responsible for promoting drug efflux into the extracellular environment. Myristicin is a natural compound isolated from nutmeg and has antiproliferative activity, which has been reported in the literature. The present study aimed to evaluate the effect of the association between myristicin and chemotherapeutic agents on the NCI/ADR-RES ovarian tumor lineage that presents a phenotype of multidrug resistance by overexpression of P-gp. It was observed that myristicin showed no cytotoxic activity for this cell line, since its IC50 was >1 mM. When myristicin was associated with the chemotherapeutic agents cisplatin and docetaxel, it potentiated their cytotoxic effects, a result evidenced by the decrease in their IC50 of 32.88% and 75.46%, respectively. Studies conducted in silico indicated that myristicin is able to bind and block the main protein responsible for MDR, P-glycoprotein. In addition, the molecule fits five of the pharmacokinetic parameters established by Lipinski, indicating good membrane permeability and bioavailability. Our hypothesis is that, by blocking the extrusion of chemotherapeutic agents, it allows these agents to freely enter cells and perform their functions, stopping the cell cycle. Considering the great impasse in the chemotherapeutic treatment of cancer that is the MDR acquired by tumor cells, investigating effective targets to circumvent this resistance remains a major challenge that needs to be addressed. Therefore, this study encourages further investigation of myristicin as a potential reverser of MDR.

Human Metabolism and Excretion of Kawakawa (Piper excelsum) Leaf Chemicals

“…[6,7] At nontoxic levels, they are reported to exhibit antiinflammatory, [8,9] antiproliferative, and anticancer effects. [10,11] Vitexin, an apigenin flavone glucoside, is a key component of several edible and medicinal plants such as pearl millet and chasteberry. [12] It has been reported to exhibit antioxidant, anticonvulsant, antiinflammatory activity, and to regulate neuroinflammation [13,14] and have antidiabetic properties.…”

Triphenylphosphine Derivatives of Allylbenzenes Express Antitumor and Adjuvant Activity When Solubilized with Cyclodextrin-Based Formulations

“…Modern therapeutic strategies are in some cases ineffective against bacterial infections and cancers, with such cases being most often associated with multiple drug resistance (MDR) [1][2][3][4][5][6][7][8][9][10][11]. Resistance mechanisms that reduce the likelihood of a patient's being cured can be divided into two groups [12]: (i) cellular metabolism (transferases, topoisomerases, growth factors), which alters the mechanism of action of the drugs or interferes with their action, and (ii) a decrease in the intracellular concentration of the drug. The drug enters the intracellular medium through the transport channels of the plasma membrane, in which Pharmaceuticals 2023, 16, 1651 2 of 20 pump proteins (ATP-binding cassette protein [4,13]) can be expressed, pumping the drug out of the cell and thus reducing its effect [4,5,[14][15][16][17].…”