Advances in understanding the role of P-gp in doxorubicin resistance: Molecular pathways, therapeutic strategies, and prospects. Issue 2 (February 2022)

• Record Type: Journal Article
• Authors: Mirzaei, Sepideh; Gholami, Mohammad Hossein; Hashemi, Farid; Zabolian, Amirhossein; Farahani, Mahdi Vasheghani; Hushmandi, Kiavash; Zarrabi, Ali; Goldman, Aaron; Ashrafizadeh, Milad; Orive, Gorka
• Is Part Of: Drug discovery today. Volume 27:Issue 2(2022)
• Page Start: 436
• Page End: 455
• Publication Date: 2022-02
• Subjects: Drugs -- Design -- Periodicals; Drugs -- Research -- Periodicals; 615.1
• DOI: 10.1016/j.drudis.2021.09.020
• Languages: English
• ISSNs: 1359-6446

Abstract

Graphical abstract: Highlights: Increased expression of P-gp leads to chemoresistance. P-gp overexpression mediates doxorubicin (DOX) resistance. Upstream mediators affect P-gp-mediated DOX resistance. Anti-tumor agents inhibit P-gp expression. Nanostructures mediate targeted regulation of P-gp. Abstract: P-glycoprotein (P-gp) is a drug efflux transporter that triggers doxorubicin (DOX) resistance. In this review, we highlight the molecular avenues regulating P-gp, such as Nrf2, HIF-1α, miRNAs, and long noncoding (lnc)RNAs, to reveal their participation in DOX resistance. These antitumor compounds and genetic tools synergistically reduce P-gp expression. Furthermore, ATP depletion impairs P-gp activity to enhance the antitumor activity of DOX. Nanoarchitectures, including liposomes, micelles, polymeric nanoparticles (NPs), and solid lipid nanocarriers, have been developed for the co-delivery of DOX with anticancer compounds and genes enhancing DOX cytotoxicity. Surface modification of nanocarriers, for instance with hyaluronic acid (HA), can promote selectivity toward cancer cells. We discuss these aspects with a focus on P-gp expression and activity.