Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

Overview

Journal Life (Basel)

Specialty Biology

Date 2022 Jun 24

PMID 35743927

Authors

Chenmala Karthika

Raman Sureshkumar

Mehrukh Zehravi

Rokeya Akter

Faraat Ali

Sarker Ramproshad

Banani Mondal

Priti Tagde

Zubair Ahmed

Farhat S Khan

Md Habibur Rahman

Simona Cavalu

Affiliations

Soon will be listed here.

Abstract

P-glycoprotein (P-gp) is a major factor in the multidrug resistance phenotype in cancer cells. P-gp is a protein that regulates the ATP-dependent efflux of a wide range of anticancer medicines and confers resistance. Due to its wide specificity, several attempts have been made to block the action of P-gp to restore the efficacy of anticancer drugs. The major goal has been to create molecules that either compete with anticancer medicines for transport or function as a direct P-gp inhibitor. Despite significant in vitro success, there are presently no drugs available in the clinic that can "block" P-gp-mediated resistance. Toxicity, unfavourable pharmacological interactions, and a variety of pharmacokinetic difficulties might all be the reason for the failure. On the other hand, P-gp has a significant effect in the body. It protects the vital organs from the entry of foreign bodies and other toxic chemicals. Hence, the inhibitors of P-gp should not hinder its action in the normal cells. To develop an effective inhibitor of P-gp, thorough background knowledge is needed in this field. The main aim of this review article was to set forth the merits and demerits of the action of P-gp on cancer cells as well as on normal cells. The influence of P-gp on cancer drug delivery and the contribution of P-gp to activating drug resistance were also mentioned.

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References

Lagares L, Perez-Castillo Y, Minovski N, Novic M . Structure-Function Relationships in the Human P-Glycoprotein (ABCB1): Insights from Molecular Dynamics Simulations. Int J Mol Sci. 2022; 23(1). PMC: 8745603. DOI: 10.3390/ijms23010362. View

Fu D . Where is it and How Does it Get There - Intracellular Localization and Traffic of P-glycoprotein. Front Oncol. 2014; 3:321. PMC: 3874554. DOI: 10.3389/fonc.2013.00321. View

Jorgovanovic D, Song M, Wang L, Zhang Y . Roles of IFN-γ in tumor progression and regression: a review. Biomark Res. 2020; 8:49. PMC: 7526126. DOI: 10.1186/s40364-020-00228-x. View

Xia D, Zhou F, Esser L . Emerging consensus on the mechanism of polyspecific substrate recognition by the multidrug transporter P-glycoprotein. Cancer Drug Resist. 2022; 2(3):471-489. PMC: 8992534. DOI: 10.20517/cdr.2019.22. View

Islam M, Islam F, Nafady M, Akter M, Mitra S, Das R . Natural Small Molecules in Breast Cancer Treatment: Understandings from a Therapeutic Viewpoint. Molecules. 2022; 27(7). PMC: 9000328. DOI: 10.3390/molecules27072165. View

Behl T, Kaur I, Sehgal A, Kumar A, Uddin M, Bungau S . The Interplay of ABC Transporters in Aβ Translocation and Cholesterol Metabolism: Implicating Their Roles in Alzheimer's Disease. Mol Neurobiol. 2020; 58(4):1564-1582. DOI: 10.1007/s12035-020-02211-x. View

Dunk C, Pappas J, Lye P, Kibschull M, Javam M, Bloise E . P-Glycoprotein (P-gp)/ABCB1 plays a functional role in extravillous trophoblast (EVT) invasion and is decreased in the pre-eclamptic placenta. J Cell Mol Med. 2018; 22(11):5378-5393. PMC: 6201374. DOI: 10.1111/jcmm.13810. View

Pyun J, McInnes L, Donnelly P, Mawal C, Bush A, Short J . Copper bis(thiosemicarbazone) complexes modulate P-glycoprotein expression and function in human brain microvascular endothelial cells. J Neurochem. 2022; 162(3):226-244. PMC: 9540023. DOI: 10.1111/jnc.15609. View

Mirzaei S, Gholami M, Hashemi F, Zabolian A, Farahani M, Hushmandi K . Advances in understanding the role of P-gp in doxorubicin resistance: Molecular pathways, therapeutic strategies, and prospects. Drug Discov Today. 2021; 27(2):436-455. DOI: 10.1016/j.drudis.2021.09.020. View

10.

Estevinho M, Fernandes C, Silva J, Gomes A, Afecto E, Correia J . Role of ATP-binding Cassette Transporters in Sorafenib Therapy for Hepatocellular Carcinoma: An Overview. Curr Drug Targets. 2021; 23(1):21-32. DOI: 10.2174/1389450122666210412125018. View

11.

Xenaki K, Dorrestijn B, Muns J, Adamzek K, Doulkeridou S, Houthoff H . Homogeneous tumor targeting with a single dose of HER2-targeted albumin-binding domain-fused nanobody-drug conjugates results in long-lasting tumor remission in mice. Theranostics. 2021; 11(11):5525-5538. PMC: 8039960. DOI: 10.7150/thno.57510. View

12.

Hsin C, Stoffel M, Gazzaz M, Schaeffeler E, Schwab M, Fuhr U . Combinations of common SNPs of the transporter gene ABCB1 influence apparent bioavailability, but not renal elimination of oral digoxin. Sci Rep. 2020; 10(1):12457. PMC: 7385621. DOI: 10.1038/s41598-020-69326-y. View

13.

Nguyen T, Duong V, Maeng H . Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability. Pharmaceutics. 2021; 13(7). PMC: 8309061. DOI: 10.3390/pharmaceutics13071103. View

14.

Kang J, Llewellyn E, Chen J, Olinares P, Brewer J, Chait B . Structural basis for transcription complex disruption by the Mfd translocase. Elife. 2021; 10. PMC: 7864632. DOI: 10.7554/eLife.62117. View

15.

Zuo H, Huang H, Lin Y, Cai X, Kong X, Luo D . Enzyme Activity of Natural Products on Cytochrome P450. Molecules. 2022; 27(2). PMC: 8779343. DOI: 10.3390/molecules27020515. View

16.

Czuba L, Hillgren K, Swaan P . Post-translational modifications of transporters. Pharmacol Ther. 2018; 192:88-99. PMC: 6263853. DOI: 10.1016/j.pharmthera.2018.06.013. View

17.

El-Readi M, Al-Abd A, Althubiti M, Almaimani R, Al-Amoodi H, Ashour M . Multiple Molecular Mechanisms to Overcome Multidrug Resistance in Cancer by Natural Secondary Metabolites. Front Pharmacol. 2021; 12:658513. PMC: 8176113. DOI: 10.3389/fphar.2021.658513. View

18.

Chakravarty M, Vora A . Nanotechnology-based antiviral therapeutics. Drug Deliv Transl Res. 2020; 11(3):748-787. PMC: 7398286. DOI: 10.1007/s13346-020-00818-0. View

19.

Vera A, Gupta P, Lei Z, Liao D, Narayanan S, Teng Q . Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo. Cancer Lett. 2018; 442:91-103. PMC: 6348084. DOI: 10.1016/j.canlet.2018.10.020. View

20.

Taylor J, Bebawy M . Proteins Regulating Microvesicle Biogenesis and Multidrug Resistance in Cancer. Proteomics. 2018; 19(1-2):e1800165. DOI: 10.1002/pmic.201800165. View