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.

• Authors: Hang Zhang, Haiwei Xu, Charles R Ashby Jr, Yehuda G Assaraf, Zhe-Sheng Chen, Hong-Min Liu
• Journal: Medicinal research reviews (Med Res Rev) Vol. 41 Issue 1 Pg. 525-555 (01 2021) ISSN: 1098-1128 [Electronic] United States
• PMID: 33047304 (Publication Type: Journal Article, Review)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents

Topics

• ATP Binding Cassette Transporter, Subfamily B (pharmacology, therapeutic use)
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Humans
• Neoplasms (drug therapy)