Research progress on the mechanisms of action, pharmacological activities and clinical application of P-glycoprotein inhibitors.

Chemotherapy is an important means of cancer treatment, but multidrug resistance (MDR) is a key factor in chemotherapy failure. The mechanisms responsible for MDR are complex. The overexpression of P-glycoprotein (P-gp) is the main driving factor. P-gp significantly reduces efficacy through efflux chemotherapy drugs. Inhibition of P-gp efflux has become one of the main strategies to reverse MDR. Over the past few decades, researchers have designed and developed a large number of P-gp inhibitors. This article reviews the P-gp inhibitors that have been widely reported in recent years and evaluates their pharmacological characteristics, mechanisms of action and clinical studies. Although numerous studies have shown that most P-gp inhibitors exhibit excellent reversal activity in vitro trials, they have not significantly improved patient conditions in clinical trials, indicating that there are currently no safe and effective drugs available in clinical practice. In recent years, structure-activity relationship (SAR) studies suggest that the quinoline ring or tetrahydroisoquinoline ring can serve as the core pharmacological factors (active mother rings) that inhibit P-gp efflux and structural modification is an important pathway to enhance reversal activity. Based on this, the article aims to provide reference for the development of new efficient and low toxicity inhibitors, and promote the clinical translation of MDR reversal strategies.