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.

Keywords: P‑glycoprotein; chemotherapy; mechanisms; multidrug resistance; tumor.

Figure 1

Overexpression of P-gp in liver cancer, lung cancer, breast cancer, gastric cancer, bowel cancer and osteosarcoma results in resistance to multiple chemotherapies. There are three ways to reverse P-gp-mediated resistance to chemotherapies: i) Inhibiting the efflux function of P-gp; ii) inhibiting P-gp expression; iii) silencing MDR genes. MDR, multidrug resistance; P-gp, P-glycoprotein.

Figure 2

Upregulation of P-gp pumps chemotherapeutic drugs out of cells, reducing the intracellular concentration of chemotherapeutic drugs and leading to chemotherapeutic drug resistance. There are three ways to reverse P-gp mediated chemotherapy resistance: (1) Inhibiting the activity of P-gp; (2) inhibiting the expression of P-gp; (3) silencing or knocking out the ABCB1 gene. These ways increase the concentration of intracellular chemotherapy drugs and reverses resistance to chemotherapy drugs. MDR, multidrug resistance; P-gp, P-glycoprotein; NBD, nucleotide-binding domains; TMD, transmembrane domain; RNAi, RNA interference; miRNA, microRNA; lncRNA, long non-coding RNA; siRNA, small interfering RNA.

Figure 3

External and internal factors activate or inhibit some signaling pathways, thus upregulating P-gp expression and promoting chemotherapy drug resistance. MDR, multidrug resistance; P-gp, P-glycoprotein; NBD, nucleotide-binding domains; TMD, transmembrane domain.