Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp)

Abstract

Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐glycoprotein (P‐gp/ABCB1) has been most well‐established. The clinical co‐administration of P‐gp drug efflux inhibitors, in combination with anticancer drugs which are P‐gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P‐gp‐mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P‐gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure–activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P‐gp inhibitors in the past 5 years. The development of P‐gp inhibitors will increase our knowledge of the mechanisms and functions of P‐gp‐mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P‐gp transporter overexpression has been implicated in MDR.

Subcellular distribution of ezrin/radixin/moesin and their roles in the cell surface localization and transport function of P-glycoprotein in human colon adenocarcinoma LS180 cells

“…P-glycoprotein (P-gp/ABCB1/MDR1) belongs to the ATP-binding cassette (ABC) transporter superfamily, which actively exports structurally and functionally unrelated chemotherapeutic drugs from cancer cells to the extracellular space [13,14]. Among the complex and multifactorial mechanisms underlying MDR, overexpression of P-gp in the cancer cell membrane has long been recognized as the principal factor responsible for MDR in a variety of cancers [15][16][17][18].…”

Quinolin-2-one-pyrimidine Hybrids Acting as Potent Reversal Agents on the P-gp-mediated Multidrug Resistance: Insights into Structure-activity Relationships and the Binding Mode

“…It has been previously described that the number of hydrogen bond acceptor methoxy groups on terminal phenyl rings is favorable for P-gp inhibitory activity [21][22][23] . Re ecting this, compound 5c, bearing two OCH 3 groups, displayed pronounced activity, followed by 5b with one methoxy and then compound 5a lacking this substituent (MECs = 0.31, 0.62 and 2.50 µM, respectively).…”

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

“…One of the causes found is due to the increase in the efflux of several chemotherapeutic drugs by the superfamily of the transmembrane transporter of ATP-binding cassettes (ABC), where P-gp is the main highlight. The administration of P-gp drug efflux inhibitors is considered a type of treatment to overcome multidrug resistance in anticancer therapy, blocking the efflux of multiple P-gp-mediated drugs [ 18 ].…”