Natural P-glycoprotein Inhibitors in Circumventing Multidrug Resistance

Abstract

Introduction: Multidrug resistance (MDR) remains a formidable challenge in pharmaceutical intervention and continues to hinder the successful clinical management of many diseases, particularly cancer.  P-glycoprotein (P-gp), a 170-kilodalton ATP-driven integral membrane protein, is a key regulator of MDR, functioning as a protective barrier against xenobiotics. Its overexpression in cancer cells markedly reduces intracellular concentrations of chemotherapeutic drugs, thereby limiting their effectiveness. Understanding the molecular mechanisms underlying drug resistance is vital for formulating approaches that can overcome this obstacle and enhance treatment outcomes. Natural inhibitors, known for their minimal toxicity and easy accessibility, hold significant potential for semi-synthetic modification. Such derivatives may provide new scaffolds valuable for developing effective MDR reversal agents.

Objectives: This review aims to provide a scientifically curated overview of natural P-gp inhibitors, emphasizing their mechanistic pathways and binding interactions involved in MDR reversal.

Methods: Findings from extensive in vitro, in vivo and in silico studies highlight the therapeutic potential of 100 natural P-gp inhibitors derived from 200 medicinal plants.

Results: Several bioactive compounds demonstrated promising MDR-modulatory properties. Detailed insights into their interactions with key residues of P-gp, may facilitate rational drug design and inform synergistic combination therapies.

Conclusions: This review serves as an essential resource for researchers in pharmaceutical sciences and drug discovery, highlighting the potential of natural bioactive molecules in circumvention of drug resistance. Leveraging nature’s pharmacological arsenal may lead to more effective, safer, sustainable therapeutic strategies with reduced reliance on synthetic inhibitors that pose toxicological concerns, ultimately enhancing clinical outcomes in conditions associated with MDR.