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Molecules (Basel, Switzerland) Nov 2023P-glycoprotein (P-gp) is a crucial membrane transporter situated on the cell's apical surface, being responsible for eliminating xenobiotics and endobiotics. P-gp... (Review)
Review
P-glycoprotein (P-gp) is a crucial membrane transporter situated on the cell's apical surface, being responsible for eliminating xenobiotics and endobiotics. P-gp modulators are compounds that can directly or indirectly affect this protein, leading to changes in its expression and function. These modulators can act as inhibitors, inducers, or activators, potentially causing drug-drug interactions (DDIs). This comprehensive review explores diverse models and techniques used to assess drug-induced P-gp modulation. We cover several approaches, including , , , and methods, with their respective strengths and limitations. Additionally, we explore the therapeutic implications of DDIs involving P-gp, with a special focus on the renal and intestinal elimination of P-gp substrates. This involves enhancing the removal of toxic substances from proximal tubular epithelial cells into the urine or increasing the transport of compounds from enterocytes into the intestinal lumen, thereby facilitating their excretion in the feces. A better understanding of these interactions, and of the distinct techniques applied for their study, will be of utmost importance for optimizing drug therapy, consequently minimizing drug-induced adverse and toxic effects.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Membrane Transport Proteins; ATP Binding Cassette Transporter, Subfamily B; Kidney; Drug Interactions
PubMed: 38005253
DOI: 10.3390/molecules28227532 -
Journal of Chemical Information and... Oct 2020The efflux transporter P-glycoprotein (P-gp) is responsible for the extrusion of a wide variety of molecules, including drug molecules, from the cell. Therefore,...
The efflux transporter P-glycoprotein (P-gp) is responsible for the extrusion of a wide variety of molecules, including drug molecules, from the cell. Therefore, P-gp-mediated efflux transport limits the bioavailability of drugs. To identify potential P-gp substrates early in the drug discovery process, models have been developed based on structural and physicochemical descriptors. In this study, we investigate the use of molecular dynamics fingerprints (MDFPs) as an orthogonal descriptor for the training of machine learning (ML) models to classify small molecules into substrates and nonsubstrates of P-gp. MDFPs encode the information from short MD simulations of the molecules in different environments (water, membrane, or protein pocket). The performance of the MDFPs, evaluated on both an in-house dataset (3930 compounds) and a public dataset from ChEMBL (1114 compounds), is compared to that of commonly used 2D molecular descriptors, including structure-based and property-based descriptors. We find that all tested classifiers interpolate well, achieving high accuracy on chemically diverse subsets. However, by challenging the models with external validation and prospective analysis, we show that only tree-based ML models trained on MDFPs or property-based descriptors generalize well to regions of the chemical space not covered by the training set.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Machine Learning; Molecular Dynamics Simulation; Prospective Studies
PubMed: 32786699
DOI: 10.1021/acs.jcim.0c00525 -
Journal of Veterinary Pharmacology and... Jul 2023The P-glycoprotein (P-gp) substrate status of antineoplastic drugs intended for veterinary patients is an important characteristic to define for two reasons. First,...
The P-glycoprotein (P-gp) substrate status of antineoplastic drugs intended for veterinary patients is an important characteristic to define for two reasons. First, neoplastic cells expressing P-gp can actively efflux drugs that are P-gp substrates curtailing their efficacy. Second, antineoplastic drugs tend to have a narrow therapeutic index. Antineoplastic drugs that are P-gp substrates can cause severe adverse reactions in animals with P-gp dysfunction such as dogs with ABCB1-1Δ and cats with ABCB11930_1931del TC. Animals with P-gp dysfunction experience greater overall exposure to P-gp substrate drugs due to mechanisms such as increased intestinal absorption, decreased biliary clearance and greater central nervous system penetration compared with animals with normal P-gp function. Accordingly, knowing the P-gp substrate status of antineoplastic drugs is an important safety consideration prior to use in canine or feline cancer patients. This study used a cell line overexpressing canine P-gp to assess the P-gp substrate status of verdinexor. Based on both a cytotoxicity assay and a competitive flow cytometry assay verdinexor is not a substrate for canine P-gp.
Topics: Animals; Dogs; Cats; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B; Acrylamides; Hydrazines
PubMed: 36924353
DOI: 10.1111/jvp.13123 -
Epilepsy Research Mar 2022Frontal lobe epilepsy (FLE) is the second most frequent type of epilepsy and the surgical outcome depends on the etiology. For instance, patients with posttraumatic FLE...
Frontal lobe epilepsy (FLE) is the second most frequent type of epilepsy and the surgical outcome depends on the etiology. For instance, patients with posttraumatic FLE (PTE) have a worse surgical outcome compared to patients with FLE related to a tumoral lesion (TL). The present study focuses to determine if the FLE etiology is associated with the P-glycoprotein (P-gp) expression, a condition associated with drug resistance. P-gp expression and cellular localization were determined by Western Blot and immunohistochemical experiments in cortical brain samples obtained from patients with PTE (n = 5), TL (n = 5), and autopsies (n = 5). The neuronal count was estimated by Nissl and stereology procedure. Results showed that the autopsies tissue showed a neuronal count of 3514 ± 304.2 neurons per mm. The P-gp expression ratio was 0.33 ± 0.02. Its expression was found in endothelial cells. Negligible P-gp expression was detected in neurons and astrocytes. Compared to the autopsies group, the TL group showed no changes in the neuronal count but, there was a decreased P-gp expression ratio (46%, p < 0.05). P-gp was located mainly in neurons, slight in astroglial, and endothelial cells. The PTE group showed a similar P-gp expression ratio compared to the autopsies group. P-gp was expressed in neurons, astrocytes, and endothelial cells in these samples. However, experiments revealed a high P-gp expression in a lower neuronal count (38%, p < 0.05 vs autopsy group). The present study reveals that patients with PTE present neuronal P-gp overexpression. This finding could underlie their worst surgical outcome.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Endothelial Cells; Epilepsy, Frontal Lobe; Frontal Lobe; Humans; Neocortex; Neurons
PubMed: 35220206
DOI: 10.1016/j.eplepsyres.2022.106892 -
Journal of Pharmaceutical Sciences Jan 2024This report focuses on pharmacokinetic drug-endogenous substrate interactions (DEIs). We hypothesized that P-glycoprotein (P-gp)-mediated DEI might affect androgen...
This report focuses on pharmacokinetic drug-endogenous substrate interactions (DEIs). We hypothesized that P-glycoprotein (P-gp)-mediated DEI might affect androgen kinetics, especially its blood-brain barrier (BBB) permeability. The intracellular accumulation of the endogenous substrates of P-gp, testosterone (TES) and androstenedione (ADO) was increased by several tested drugs in uptake studies using P-gp overexpressing cells, indicating that these drugs inhibit P-gp-mediated efflux of TES of ADO from the cells. In a transport study using rat BBB kit, we found that the BBB limited the penetration of TES and ADO into the central nervous system. In addition, tested drugs that cause DEI were found to increase BBB permeability of TES and ADO via P-gp inhibition. In short, this study provides new findings regarding the possibility that DEI may affect the kinetics of endogenous substrates of P-gp.
Topics: Rats; Animals; Blood-Brain Barrier; Androgens; Biological Transport; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Permeability; Testosterone
PubMed: 37898165
DOI: 10.1016/j.xphs.2023.10.034 -
Phytomedicine : International Journal... Sep 2022Previously, we have investigated the anti-tumor activity and mechanism through which dandelion acts against triple-negative breast cancer (TNBC). However, traditional...
BACKGROUND
Previously, we have investigated the anti-tumor activity and mechanism through which dandelion acts against triple-negative breast cancer (TNBC). However, traditional Chinese medicine is mostly accepted as an adjunct therapy during chemotherapy in clinical practice. So far, little is known about the effects of dandelion in conjunction with chemotherapeutic drugs.
PURPOSE
To investigate the effects of dandelion on the anti-tumor activity and cardiotoxicity of doxorubicin (DOX), and to further explore the molecular mechanisms through which these effects occur.
STUDY DESIGN
At the beginning of this study, dandelion was observed to alleviate DOX-induced cardiotoxicity and reduce the anti-tumor activity of DOX. Subsequently, we investigated whether the resistance to DOX mediated by P-glycoprotein was involved in the above effects.
METHODS
The cardioprotective effect of dandelion was investigated on DOX-treated mice by histological analysis, myocardial enzyme assays, and an untargeted metabolomics study based on LC-Q-TOF/MS. TNBC cell lines and 4T1 tumor-bearing mice were employed to investigate the combined anti-tumor activity. Laser scanning confocal microscope and a flow cytometry analysis were employed to measure the intracellular accumulation of DOX. A specific, sensitive, and rapid LC-MS/MS method was developed to detect the efflux of DOX from cells. Expression of P-glycoprotein in mouse tumor and heart tissues was detected via Western blotting analysis.
RESULTS
Dandelion was found to significantly alleviate DOX-induced cardiotoxicity, as was evidenced by improved cardiomyocyte morphology, decreased LDH and CK-MB release, and adjusted metabolic biomarker levels. However, in vitro and in vivo studies showed that dandelion could reduce the anti-tumor activity of DOX. This counteraction was achieved by activating of the drug efflux transporter P-glycoprotein, thereby promoting the efflux of DOX from cells and reducing the intracellular accumulation of DOX. Moreover, the activation of P-glycoprotein by dandelion in mouse heart tissue was also observed, thus suggesting that the decrease of cardiac DOX accumulation plays an important role in the cardioprotective effect of dandelion.
CONCLUSION
Dandelion can activate the P-glycoprotein in heart and tumor tissues, which ameliorates DOX-induced cardiotoxicity but attenuates DOX cytotoxicity toward TNBC. Our findings have important implications for the correct clinical use of dandelion.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Apoptosis; Cardiotoxicity; Chromatography, Liquid; Doxorubicin; Humans; Mice; Myocytes, Cardiac; Oxidative Stress; Tandem Mass Spectrometry; Taraxacum; Triple Negative Breast Neoplasms
PubMed: 35760022
DOI: 10.1016/j.phymed.2022.154275 -
European Journal of Medicinal Chemistry Sep 2020P-Glycoprotein (P-gp) overexpression is a major mechanism by which cancer cells acquire the multidrug resistance (MDR) phenotype, and is associated with poor clinical...
P-Glycoprotein (P-gp) overexpression is a major mechanism by which cancer cells acquire the multidrug resistance (MDR) phenotype, and is associated with poor clinical outcome in patients. In an effort to develop MDR-reversal agents, we synthesized and evaluated a series of thiophenylbenzofuran derivatives (4-31) as P-gp inhibitors, among which compounds 4, 10, and 14 represented the optimal agent in reversing the MDR phenotype. These P-gp inhibitors were dramatically effective than verapamil in sensitizing the human ABCB1-overexpressing ABCB1/Flp-In™-293 cells and MDR KBvin cells to a series of chemotherapeutic agents, including vincristine and paclitaxel, as manifested by multi-fold decreases in the respective IC values to therapeutically attainable levels.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Benzofurans; Binding Sites; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Protein Binding
PubMed: 32569926
DOI: 10.1016/j.ejmech.2020.112422 -
Neoplasia (New York, N.Y.) May 2023Multidrug resistance (MDR) hinders treatment efficacy in cancer therapy. One typical mechanism contributing to MDR is the overexpression of permeability-glycoprotein...
Multidrug resistance (MDR) hinders treatment efficacy in cancer therapy. One typical mechanism contributing to MDR is the overexpression of permeability-glycoprotein (P-gp) encoded by ATP-binding cassette subfamily B member 1 (ABCB1). Basic helix-loop-helix family member e40 (BHLHE40) is a well-known transcription factor that has pleiotropic effects including the regulation of cancer-related processes. However, whether BHLHE40 regulates MDR is still unknown. Chromatin immunoprecipitation-seq study revealed BHLHE40 occupancy in the promoter of ABCB1 gene. Adriamycin (ADM)-resistant human chronic myeloid leukemia cells (K562/A) and human breast cancer cells (MCF-7/A) were established. BHLHE40 expression was downregulated in the ADM-resistant cell lines. Overexpression of BHLHE40 resensitized resistant cells to ADM, promoted cell apoptosis in vitro and suppressed tumor growth in vivo, whereas BHLHE40 knockdown induced resistance to ADM in parental cells. Moreover, we found that BHLHE40 regulated drug resistance by directly binding to the ABCB1 promoter (-1605 to -1597) and inactivating its transcription. In consistence, the expression of BHLHE40 was negatively correlated with ABCB1 in various cancer cells, while positively with cancer cell chemosensitivity and better prognosis of patients with breast cancer. The study reveals the role of BHLHE40 as a transcriptional suppressor on the expression of ABCB1, major ABC transporter in chemoresistance. The findings extend the function of BHLHE40 in tumor progression and provides a novel mechanism for the reversal of multidrug resistance.
Topics: Humans; Female; Transcription Factors; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistance, Neoplasm; Drug Resistance, Multiple; Doxorubicin; Breast Neoplasms; Cell Line, Tumor; Homeodomain Proteins; Basic Helix-Loop-Helix Transcription Factors; ATP Binding Cassette Transporter, Subfamily B
PubMed: 36931039
DOI: 10.1016/j.neo.2023.100891 -
Molecular Pharmaceutics Jul 2022Inflammation is characterized by an increased secretion of proinflammatory cytokines known to alter the expression and functionality of drug transporters. Since...
Inflammation is characterized by an increased secretion of proinflammatory cytokines known to alter the expression and functionality of drug transporters. Since -glycoprotein (-gp) plays a key role in the pharmacokinetics of several drugs, these modulations could further affect drug exposure. In this context, this study aims to investigate the impact of in vitro cytokine exposure on the expression and activity of -gp using the intestinal model Caco-2 and the human renal cells RPTEC/TERT1. Cells were exposed to various concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1β for 24 or 72 h. Gene expression was then assessed by RT-qPCR followed by absolute quantification of -gp using liquid chromatography coupled with mass spectrometry. Then, the activity of -gp was assessed by the intracellular accumulation of rhodamine 123. TNF-α increased both the gene expression and -gp activity by 15-40% in each model. Minor modulations were observed at the protein level with increases of up to 8% for RPTEC/TERT1 cells and 24% for Caco-2 cells. Conversely, IL-1β led to a downregulation of gene, protein, and functionality by 48 and 25% in intestinal and renal cells, respectively. Taken together, these data highlighted that gene expression levels and functional activity of -gp are altered by the pro-inflammatory cytokines in intestinal and renal cells. Such pronounced changes in human -gp could result in altered exposure to drug substrates. Further in vivo studies are needed to confirm the impact of inflammation on drug pharmacokinetics.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Caco-2 Cells; Cytokines; Humans; Inflammation; Interleukin-1beta; Tumor Necrosis Factor-alpha
PubMed: 35674492
DOI: 10.1021/acs.molpharmaceut.2c00140 -
Carbohydrate Polymers Mar 2024Overcoming P-glycoprotein (P-gp)-mediated efflux poses a significant challenge for the pharmaceutical industry. This study investigates the potential of thiolated...
Overcoming P-glycoprotein (P-gp)-mediated efflux poses a significant challenge for the pharmaceutical industry. This study investigates the potential of thiolated β-cyclodextrins (β-CD-SHs) as inhibitors of P-gp-mediated efflux in Caco-2 cells. Through a series of transport assays, intracellular accumulation, and efflux of the P-gp substrates Rhodamine 123 (Rh123) and Calcein-AM with and without co-administration of β-CD-SHs were assessed. The results revealed that the cellular uptake of Rh123 and Calcein-AM were enhanced up to 7- and 3-fold, compared to the control, respectively. In efflux studies an up to 2.5-fold reduction of the Rh123 efflux was reached compared the control, indicating a substantial decrease of Rh123 efflux by β-CD-SHs. Furthermore, it was observed that β-CD-SHs led to a decrease in the reactivity of fluorescence-labeled anti-P-gp, suggesting additional effects on the conformation of P-gp. Overall, this study demonstrates the potential of β-CD-SHs as effective modulator of P-gp-mediated drug efflux in Caco-2 cells.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caco-2 Cells; Cyclodextrins; Rhodamine 123
PubMed: 38171673
DOI: 10.1016/j.carbpol.2023.121648