Carnosine Potentiates Doxorubicin-Induced Cytotoxicity in Resistant NCI/ADR-RES Cells by Inhibiting P-Glycoprotein—In Silico and In Vitro Evidence

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Abstract

The activity of the P-glycoprotein (P-gp) transporter encoded by the ABCB1 gene confers resistance to anticancer drugs and contributes to cancer-related mortality and morbidity. Recent studies revealed the cytotoxic effects of the endogenous dipeptide carnosine. The current study aimed to investigate the role of carnosine as a potential inhibitor of P-gp activity. We used molecular docking and molecular dynamic simulations to study the possible binding and stability of carnosine-P-gp interactions compared with verapamil. In vitro assays using doxorubicin-resistant NCI/ADR-RES cells were established to test the effects of carnosine (10–300 µM) on P-gp activity by the rhodamine-123 efflux assay and its effect on cell viability and doxorubicin-induced cytotoxicity. Verapamil (10 µM) was used as a positive control. The results showed that carnosine binding depends mainly on hydrogen bonding with GLU875, GLN946, and ALA871, with a higher average Hbond than verapamil. Carnosine showed significant but weaker than verapamil-induced rhodamine-123 accumulation. Carnosine and verapamil similarly inhibited cell viability. However, verapamil showed a more significant potentiating effect on doxorubicin-induced cytotoxicity than a weaker effect of carnosine at 300 µM. These results suggest that carnosine inhibits P-gp activity and potentiates doxorubicin-induced cytotoxicity at higher concentrations. Carnosine might be a helpful lead compound in the fight against multidrug-resistant cancers.

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Structural insight into substrate and inhibitor discrimination by human P-glycoprotein

Amer Alam, Julia Kowal, Eugenia V. Broude … (2019)

ABCB1, also known as P-glycoprotein, actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic drug delivery. We determined the 3.5-angstrom cryo–electron microscopy structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the nucleotide-binding domains (NBDs), revealing how the plasticity of the drug-binding site controls the dynamics of the adenosine triphosphate–hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport.

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P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers

Anna Seelig (2020)

P-glycoprotein or multidrug resistance protein (MDR1) is an adenosine triphosphate (ATP) binding cassette transporter (ABCB1) intensely investigated because it is an obstacle to successful pharmacotherapy of cancers. P-glycoprotein prevents cellular uptake of a large number of structurally and functionally diverse compounds, including most cancer therapeutics and in this way causes multidrug resistance (MDR). To overcome MDR, and thus improve cancer treatment, an understanding of P-glycoprotein inhibition at the molecular level is required. With this goal in mind, we propose rules that predict whether a compound is a modulator, substrate, inhibitor, or inducer of P-glycoprotein. This new set of rules is derived from a quantitative analysis of the drug binding and transport properties of P-glycoprotein. We further discuss the role of P-glycoprotein in immune surveillance and cell metabolism. Finally, the predictive power of the proposed rules is demonstrated with a set of FDA approved drugs which have been repurposed for cancer therapy.

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Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen.

M Grever, Angela M Alvarez, Anthony Fojo … (1995)

Identifying new chemotherapeutic agents and characterizing mechanisms of resistance may improve cancer treatment. The Anticancer Drug Screen of the National Cancer Institute uses 60 cell lines to identify new agents. Expression of mdr-1/P-glycoprotein was measured by quantitative PCR. Expression was detected in 39 cell lines; the highest levels were in renal and colon carcinomas. Expression was also detected in all melanomas and central nervous system tumors, but in only one ovarian carcinoma and one leukemia cell line. Using a modified version of the COMPARE program, a high correlation was found between expression of mdr-1 and cellular resistance to a large number of compounds. Evidence that these compounds are P-glycoprotein substrates includes: (a) enhancement of cytotoxicity by verapamil; (b) demonstration of cross-resistance in a multidrug-resistant cell line, (c) ability to antagonize P-glycoprotein, increasing vinblastine accumulation by decreasing efflux; and (d) inhibition of photoaffinity labeling by azidopine. Identification of many heretofore unrecognized compounds as substrates indicates that P-glycoprotein has a broader substrate specificity than previously recognized. This study confirms the validity of this novel approach and provides the basis for similar studies examining a diverse group of gene products, including other resistance mechanisms, putative drug targets, and genes involved in the cell cycle and apoptosis.