Mechanism of multidrug resistance to chemotherapy mediated by P‑glycoprotein (Review)

Abstract

Multidrug resistance (MDR) seriously limits the clinical application of chemotherapy. A mechanism underlying MDR is the overexpression of efflux transporters associated with chemotherapeutic drugs. P-glycoprotein (P-gp) is an ATP-binding cassette (ABC) transporter, which promotes MDR by pumping out chemotherapeutic drugs and reducing their intracellular concentration. To date, overexpression of P-gp has been detected in various types of chemoresistant cancer and inhibiting P-gp-related MDR has been suggested. The present review summarizes the mechanisms underlying MDR mediated by P-gp in different tumors and evaluated the related signaling pathways, with the aim of improving understanding of the current status of P-gp-mediated chemotherapeutic resistance. This review focuses on the main mechanisms of inhibiting P-gp-mediated MDR, with the aim of providing a reference for the study of reversing P-gp-mediated MDR. The first mechanism involves decreasing the efflux activity of P-gp by altering its conformation or hindering P-gp-chemotherapeutic drug binding. The second inhibitory mechanism involves inhibiting P-gp expression to reduce efflux. The third inhibitory mechanism involves knocking out the ABCB1 gene. Potential strategies that can inhibit P-gp include certain natural products, synthetic compounds and biological techniques. It is important to screen lead compounds or candidate techniques for P-gp inhibition, and to identify inhibitors by targeting the relevant signaling pathways to overcome P-gp-mediated MDR.

Local anaesthetics and chemotherapeutic agents: a systematic review of preclinical evidence of interactions and cancer biology

“… 28 , 29 , 58 P-glycoprotein facilitates drug efflux across the cell membrane and out of the cancer cell, thus providing a means by which drug resistance can develop and which provides a site where local anaesthetics can act to reduce P-glycoprotein activity and enhance chemotherapeutic agent efficacy. 63 …”

Deguelin Restores Paclitaxel Sensitivity in Paclitaxel-Resistant Ovarian Cancer Cells via Inhibition of the EGFR Signaling Pathway

“…113 Overexpression of the ABC transporter P-gp has also been reported in various chemoresistant cancer cells. 114,115 Extracellular efflux of anticancer agents, including paclitaxel and cisplatin, has been implicated in playing an important role in the chemoresistance of ovarian cancer. 116 In this study, we found that deguelin did not influence the expression and function of P-gp (Figure 4).…”

Novel players in the development of chemoresistance in ovarian cancer: ovarian cancer stem cells, non-coding RNA and nuclear receptors

“…Structurally, ABC transporters have single polypeptides with two nucleotide binding domains (NBDs) and two transmembrane domains (TMDs) [65] . The SNAIL, ZEBs, and SLUG promote MDR, while VDR, ER, PXR, KLF, Gli, and Sp are also known to modulate ABC transporters [66] . The altered ABCB1 structure or drug binding, inhibition of its expression or knockout of the ABCB1 gene are the most potential strategies to overcome ABCB1-mediated drug resistance [67] .…”