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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.

SUBMITTER: Seneme EF

PROVIDER: S-EPMC9612322 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Seneme Elisa Frederico EF Dos Santos Daiane Carla DC de Lima Carolina Afonso CA Zelioli Ícaro Augusto Maccari ÍAM Sciani Juliana Mozer JM Longato Giovanna Barbarini GB

Pharmaceuticals (Basel, Switzerland) 20221007 10

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 ...[more]

PMID: 36297344

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Project description:BackgroundMultidrug resistance (MDR) has been regarded as one of the major hurdles for the successful outcome of cancer chemotherapy. The collateral sensitivity (CS) effect is one the most auspicious anti-MDR strategies. Epoxylathyrane derivatives 1-16 were obtained by derivatization of the macrocyclic diterpene epoxyboetirane A (17), a lathyrane-type macrocyclic diterpene isolated from Euphorbia boetica. Some of these compounds were found to strongly modulate P-glycoprotein (P-gp/ABCB1) efflux.PurposeThe main goal was to develop lathyrane-type macrocyclic diterpenes with improved MDR-modifying activity, by targeting more than one anti-MDR mechanism.Study design/methodsIn this study, the potential CS effect of compounds 1-16 was evaluated against gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29) human cancer cells and their drug-resistant counterparts, respectively selected against mitoxantrone (EPG85-257RNOV; EPP85-181RNOV; HT-RNOV) or daunorubicin (EPG85-257RDB; EPP85-181RDB; HT-RDB). The most promising compounds (8, 15, and 16) were investigated as apoptosis inducers, using the assays annexin V/PI and active caspase-3.ResultsThe compounds were more effective against the resistant gastric cell lines, being the CS effect more significant in EPG85-257RDB cells. Taking together the IC50 values and the CS effect, compounds 8, 15, and 16 exhibited the best results. Epoxyboetirane P (8), with the strongest MDR-selective antiproliferative activity against gastric carcinoma EPG85-257RDB cells (IC50 of 0.72 µM), being 10-fold more active against this resistant subline than in sensitive gastric carcinoma cells. The CS effect elicited by compounds 15 and 16 appeared to be by inducing apoptosis via caspase-3 activation. Structure-activity relationships of the compounds were additionally obtained through regression models to clarify the structural determinants associated to the CS effect.ConclusionsThis study reinforces the importance of lathyrane-type diterpenes as lead molecules for the research of MDR-modifying agents.

Dataset Information

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

Publications

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

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