TY - JOUR. T1 - Interaction of the P-glycoprotein multidrug transporter (MDR1) with high affinity peptide chemosensitizers in isolated membranes, reconstituted systems, and intact cells. AU - Sharom, Frances J.. AU - Yu, Xiaohong. AU - Lu, Peihua. AU - Liu, Ronghua. AU - Chu, Joseph W K. AU - Szabó, Katalin. AU - Müller, M.. AU - Hose, Curtis D.. AU - Monks, Anne. AU - Váradi, A.. AU - Seprődi, J.. AU - Sarkadi, B.. PY - 1999/8/15. Y1 - 1999/8/15. N2 - P-Glycoprotein-mediated multidrug resistance can be reversed by the action of a group of compounds known as chemosensitizers. The interactions with P-glycoprotein of two novel hydrophobic peptide chemosensitizers (reversins 121 and 205) have been studied in model systems in vitro, and in a variety of MDR1-expressing intact tumor cells. The reversins bound to purified P-glycoprotein with high affinity (77-154 nM), as assessed by a quenching assay using fluorescently labeled purified protein. The peptides modulated P-glycoprotein ATPase activity ...
TY - JOUR. T1 - Inhibition of human P-glycoprotein transport and substrate binding using a galantamine dimer. AU - Namanja, Hilda A.. AU - Emmert, Dana. AU - Pires, Marcos M.. AU - Hrycyna, Christine A.. AU - Chmielewski, Jean. PY - 2009/10/30. Y1 - 2009/10/30. N2 - The human multidrug resistance transporter P-glycoprotein (P-gp) prevents the entry of compounds into the brain by an active efflux mechanism at the blood-brain barrier (BBB). Treatment of neurodegenerative diseases, therefore, has become a challenge and the development of new reversible inhibitors of P-gp is pertinent to overcome this problem. We report the design and synthesis of a crosslinked agent based on the Alzheimers disease treatment galantamine (Gal-2) that inhibits P-gp-mediated efflux from cultured cells. Gal-2 was found to inhibit the efflux of the fluorescent P-gp substrate rhodamine 123 in cancer cells that over-express P-gp with an IC50 value of approximately 0.6 μM. In addition, Gal-2 was found to inhibit the ...
TY - JOUR. T1 - P-glycoprotein expression and multidrug resistance in adrenocortical carcinoma. AU - Flynn, Stuart D. AU - Murren, J. R.. AU - Kirby, W. M.. AU - Honig, J.. AU - Kan, L.. AU - Kinder, B. K.. PY - 1992. Y1 - 1992. N2 - Background. The response of adrenocortieal carcinoma (ACC) to adjuvant chemotherapy has been disappointing with no significant impact on survival. The normal adrenal cortex has very high levels of P-glycoprotein, an energy-dependent efflux pump of a variety of structurally unrelated chemotherapeutic agents. P-glycoprotein has been implicated as a cause of multidrug resistance in a variety of neoplasms. The purpose of this study was to evaluate P-glycoprotein expression in ACC. Methods. Eleven patients with ACC had paraffin-em bedded tumor evaluated for P-glycoprotein expression. These were analyzed by immunohistochemistry assay with a battery of four anti-P-glycoprotein antibodies (MRK-16, JSB-1, UIC-2, MDR). Results. All eleven cases showed intense, predominantly ...
This study was aimed at evaluating the influence of 5637-conditioned medium (5637-CM) and human recombinant cytokines on both expression and function of P-glycoprotein (P-gp) in TF-1, a GM-CSF/IL-3-dependent acute myeloid leukemia cell line which constitutively expresses functional P-gp. P-gp expression was measured by flow cytometry using MRK16 monoclonal antibody. P-gp function was measured by rhodamine 123 (Rh 123) efflux kinetics. When TF-1 cells were cultured with 5637-CM (50% v/v), both P-gp expression and P-gp efflux capacity were increased in a time-dependent manner with a 4-fold increase in P-gp expression level at day 6 whereas TF-1 cell differentiation status remained unchanged as assessed by morphological studies, phenotypical and cytochemistry analysis. Recombinant cytokines including GM-CSF, G-CSF, IL-1 beta, IL-6, stem cell factor, LIF, erythropoietin, and IL-3 had no effect on P-gp expression whereas TNF alpha induced dose- and time-dependent P-gp and mdr-1 gene overexpression. However,
How to Cite: Karunaratne, D.N. and Audus, K.L., 2007. Use of fluorescent probes to monitor the efflux transporters P-Glycoprotein and MRP1 in Bewo cells. Journal of the National Science Foundation of Sri Lanka, 35(1), pp.19-27. DOI: http://doi.org/10.4038/jnsfsr.v35i1.3658 ...
P‐glycoprotein (Pgp) is a 170 kDa phosphorylated glycoprotein encoded by human MDR1 gene. It is responsible for the systemic disposition of numerous structurally and pharmacologically 1unrelated lipophilic and amphipathic drugs, carcinogens, toxins, and other xenobiotics in many organs, such as the intestine, liver, kidney, and brain. Like cytochrome P450s (CYP3A4), Pgp is vulnerable to inhibition, activation, or induction by herbal constituents. This was demonstrated by using an ATPase assay, purified Pgp protein or intact Pgp‐expressing cells, and proper probe substrates and inhibitors. Curcumin, ginsenosides, piperine, some catechins from green tea, and silymarin from milk thistle were found to be inhibitors of Pgp, while some catechins from green tea increased Pgp‐mediated drug transport by heterotropic allosteric mechanism, and St. Johns wort induced the intestinal expression of Pgp in vitro and in vivo. Some components (e.g., bergamottin and quercetin) from grapefruit juice were reported to
DI-fusion, le Dépôt institutionnel numérique de lULB, est loutil de référencementde la production scientifique de lULB.Linterface de recherche DI-fusion permet de consulter les publications des chercheurs de lULB et les thèses qui y ont été défendues.
P-glycoprotein (P-gp) overexpression is the most frequently observed cause of multidrug resistance in neoplastic cells. In our experiments, P-gp was expressed in L1210 mice leukemia cells (S cells) by selection with vincristine (R cells) or transfection with the gene encoding human P-gp (T cells). Remodeling of cell surface sugars is associated with P-gp expression in L1210 cells as a secondary cellular response. In this study, we monitored the alteration of cell surface saccharides by Sambucus nigra agglutinin (SNA), wheat germ agglutinin (WGA) and Maackia amurensis agglutinin (MAA). Sialic acid is predominantly linked to the surface of S, R and T cells via α-2,6 branched sugars that tightly bind SNA. The presence of sialic acid linked to the cell surface via α-2,3 branched sugars was negligible, and the binding of MAA (recognizing this branch) was much less pronounced than SNA. WGA induced greater cell death than SNA, which was bound to the cell surface and agglutinated all three L1210 cell-variants
The purpose of this work was to investigate if P-glycoprotein (Pgp) efflux pump activity could be inhibited in the sub-bronchial epithelial cell line, Calu-3, by glucocorticosteroids and β-ligands. The Pgp modulation efficiency of each compound was determined by its ability to increase the accumulation of the Pgp substrate rhodamine 123 (Rh123) accumulation in these cells. Pgp inhibition was observed at ≥ 100 μM steroids and β-ligand. The modulation effectiveness of the β-ligands increased with increasing hydrophobicity (log Poctanol/aqueous) whereas an obvious correlation was not obtained with the complete set of steroids tested. Steroidal Pgp substrates did not affect Rh123 accumulation (e.g., aldosterone, dexamethasone, 11β, 17α, 21-OH progesterone). In contrast, two hydrophobic non P-gp steroidal substrates (testosterone and progesterone) displayed different effects on Rh123 accumulation, with progesterone being the more potent modulator. The most hydrophobic β-ligand, propranolol, ...
TY - JOUR. T1 - Estradiol regulation of P-glycoprotein expression in mouse kidney and human tubular epithelial cells, implication for renal clearance of drugs. AU - Kanado, Yuki. AU - Tsurudome, Yuya. AU - Omata, Yuji. AU - Yasukochi, Sai. AU - Kusunose, Naoki. AU - Akamine, Takahiro. AU - Matsunaga, Naoya. AU - Koyanagi, Satoru. AU - Ohdo, Shigehiro. PY - 2019/11/12. Y1 - 2019/11/12. N2 - P-glycoprotein (P-gp/ABCB1) is an ATP-binding cassette drug efflux transporter expressed in a variety of tissues that affects the pharmacokinetic disposition of many drugs. Although several studies have reported gender-dependent differences in the expression of P-gp, the role of sex hormones in regulating the expression of P-gp and its transport activity has not been well understood. In this study, we demonstrated that 17β-estradiol has the ability to induce the expression of P-pg in mouse kidneys and cultured human renal proximal tubular epithelial cells. After intravenous injection of a typical P-gp ...
OBJECTIVE: In vitro and animal experiments suggest that P-glycoprotein forms a functional barrier between maternal and fetal blood circulation in the placenta, thus protecting the fetus from exposure to xenobiotics during pregnancy. In this study we aimed to characterize the role of P-glycoprotein in the blood-placental barrier by use of dually perfused human placenta. METHODS: Twenty-eight human placentas were obtained after delivery, and both the maternal side and the fetal side were perfused for 2 hours. Saquinavir was used as a probe drug for P-glycoprotein-dependent active transfer, and PSC833 (valspodar) or GG918 was used as an inhibitor of P-glycoprotein function in a maternal-to-fetal and fetal-to-maternal perfusion setting. Genotyping for ABCB1 (C3435T and G2677A/T) polymorphism and quantification of P-glycoprotein expression were done for each placenta. RESULTS: The fetal-to-maternal transfer of saquinavir was 108-fold higher (P = .003) compared with transfer from the maternal to the ...
Drug resistance is a major problem in cancer chemotherapy. Treatment protocols generally include a number of different cytotoxic drugs given in combination. Therefore, drug resistance in the tumor is likely to result from the coexpression of several cellular activities able to prevent cell killing by any of the drugs used. In this study we have measured several potential drug resistance mechanisms consisting of the multidrug resistance gene product P-glycoprotein, glutathione, glutathione-transferase and -peroxidase, and the DNA repair enzyme O6-alkylguanine-DNA-alkyltransferase in samples of colon carcinoma and normal adjacent mucosa from 23 untreated patients. All of these, with the exception of P-glycoprotein, showed significant increases in tumor tissue levels when compared with normal tissue from the same patient. The significance was highest for glutathione peroxidase (P less than or equal to 0.0005). Individual patients, however, showed very different patterns, with none, several, or all ...
Inhibition of intestinal P-glycoprotein might enhance the absorption of orally administered P-glycoprotein substrate drugs. We show here a 10-fold increased oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. These results encourage further research on the …
TY - JOUR. T1 - Topological folding and proteolysis profile of P-glycoprotein in membranes of multidrug-resistant cells. T2 - Implications for the drug-transport mechanism. AU - Zhang, Mei. AU - Wang, Guichun. AU - Shapiro, Adam. AU - Zhang, Jian-Ting. PY - 1996. Y1 - 1996. N2 - P-glycoprotein (Pgp)1 is a polytopic membrane protein and functions as an energy-dependent drug efflux pump. It is responsible for multidrug resistance (MDR) in cancer cell lines. Recently, the topological structure of Pgp has been investigated. However, the results are in dispute. A major question concerning the Pgp topology is the membrane orientation of the loop linking TM4 and TM5 (loop 4) and the loop linking TM8 and TM9 (loop 8). In this study, we generated polyclonal antibodies specific to these two loops. In combination with a panel of other well-characterized site-specific polyclonal and monoclonal antibodies of Pgp, we tested the membrane orientation of these two loops of Pgp in multidrug-resistant cells using ...
The ATP-binding cassette (ABC) transporter ABCB1, encoded by the multidrug resistance gene MDR1, is expressed on brain microvascular endothelium and several types of epithelium, but not on endothelia outside the CNS. It is an essential component of the blood-brain barrier. The aim of this study was to identify cell-specific controls on the transcription of MDR1 in human brain endothelium. Reporter assays identified a region of 500bp around the transcription start site that was optimally active in brain endothelium. Chromatin immunoprecipitation identified Sp3 and TFIID associated with this region and EMSA (electrophoretic mobility shift assays) confirmed that Sp3 binds preferentially to an Sp-target site (GC-box) on the MDR1 promoter in brain endothelium. This result contrasts with findings in other cell types and with the colon carcinoma line Caco-2, in which Sp1 preferentially associates with the MDR1 promoter. Differences in MDR1 transcriptional control between brain endothelium and Caco-2 ...
Expression of the multidrug transporter P-glycoprotein (P-gp) is one of the major causes of multidrug resistance in cancer cells. P-gp is a 170-kDa membrane protein encoded by the MDR1 gene in humans. Based on its sequence and domain organization, P-gp is classified as a member of ATP binding cassette superfamily; it consists of two symmetrical halves, each half containing six transmembrane (TM) domains and a cytoplasmic nucleotide binding domain. Although most members of the ABC transporter family have stringent substrate specificities, P-gp recognizes many compounds, including anthracyclines (e.g., doxorubicin and daunomycin), vinca alkaloids (e.g., vincristine and vinblastine), antibiotics (e.g., actinomycin D), circular and toxic peptides (e.g., valinomycin and gramicidin), and relatively noncytotoxic agents such as verapamil, azidopine, quinidine, and cyclosporin A. These P-gp substrates have no common chemical structure. They are all low-molecular-weight nonanionic hydrophobic or ...
Good Morning David, Ive done several years of Multi Drug Resistance Protein work. It was a tough nut to crack back a few years ago. We use JSB-1 primary antibody [far superior to C219] and the procedure is long... weve added extra IgG fragments to give the DAB some extra places to bind. Its really a nice, clean, amplified method. I can send you the worksheet for the procedure if youd like. Please find the related publications below (methods paper is #2). I think #3 may be of special interest to you. 1)Toth, K., Vaughan, M.M., Slocum, H.K., Fredericks, W.J., Chen, Y., Arredondo, M.A., Harstrick, A., Karakousis, C., Baker, R.M., Rustum, Y.M. Comparison of an Immunoperoxidase sandwich Staining Method and Western Blot Detection of P-glycoprotein in Human Cell Lines and Sarcomas. Amer. J. Path. 140:1009-1016, 1992. 2)Toth, K., Vaughan, M.M., Slocum, H.K., Arredondo, M.A., Takita, H., Baker, R.M., Tsuro, T., and Rustum, Y.M. New Immunohistochemical Sandwich Staining Method for MDR1 ...
Our study demonstrated that rIL2, administered at 9 MIU/kg twice a day intraperitoneally for 4 days in mice, induces a 2-fold decrease in the protein expression of intestinal Pgp. This lower Pgp protein expression led to a 1.6-fold decrease in Pgp activity measured in vitro with everted gut sacs. This decreased Pgp activity was associated with increased digoxin and saquinavir bioavailabilities in mice pretreated with rIL2. This is the first in vivo report where a decrease in intestinal Pgp activity is shown to be induced by a decrease in Pgp protein expression.. In the present study, we have developed a new in vitro model to study the intestinal Pgp function of mice. Rat everted gut sacs have already been used, especially with rhodamine 123 as Pgp substrate (Yumoto et al., 1999; Veau et al., 2001). Conversely, mouse intestine had never been used in the same model until now. The secretion of rhodamine 123 across everted mouse intestine was strongly inhibited by verapamil and cyclosporin A, both ...
[18F]Fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid; anti-[18F]FACBC), a positron emission tomography tracer used for the diagnosis of recurrent prostate cancer, is transported via amino acid transporters (AATs) with high affinity (Km: 97-230 μM). However, the mechanism underlying urinary excretion is unknown. In this study, we investigated the involvement of AATs and drug transporters in renal [18F]fluciclovine reuptake. [14C]Fluciclovine (trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid) was used because of its long half-life. The involvement of AATs in [14C]fluciclovine transport was measured by apical-to-basal transport using an LLC-PK1 monolayer as model for renal proximal tubules. The contribution of drug transporters herein was assessed using vesicles/cells expressing the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), organic anion transporter 1 (OAT1), organic anion transporter 3
This Application Note demonstrates how to measure P-glycoprotein (Pgp) Inhibition fast and simple on a Microplate Reader. Read more.
HIV-1 is shed in genital secretions which increase the risk of transmission between sexual partners and from mother to infant. Antiretroviral medication taken prior to exposure to HIV-1 can prevent viral transmission from a mother to her infant. Raltegravir (RAL), by blocking integration of viral cDNA into the hosts genome, makes an excellent candidate for preventing HIV-1 infection. RAL is licensed for treatment with twice-daily dosing based on plasma trough concentrations; however, intracellular concentrations of RAL which are relevant to blocking infection of cells have not been previously studied. P-glycoprotein pumps, which are involved in regulating drug absorption and metabolism, can influence intracellular drug concentrations. P-glycoprotein concentrations appear to vary with menstrual cycle suggesting it may affect intracellular drug concentration of RAL in women.. Women will be enrolled in the study and followed during the course of a menstrual cycle while taking a dose of 400mg PO ...
HIV-1 is shed in genital secretions which increase the risk of transmission between sexual partners and from mother to infant. Antiretroviral medication taken prior to exposure to HIV-1 can prevent viral transmission from a mother to her infant. Raltegravir (RAL), by blocking integration of viral cDNA into the hosts genome, makes an excellent candidate for preventing HIV-1 infection. RAL is licensed for treatment with twice-daily dosing based on plasma trough concentrations; however, intracellular concentrations of RAL which are relevant to blocking infection of cells have not been previously studied. P-glycoprotein pumps, which are involved in regulating drug absorption and metabolism, can influence intracellular drug concentrations. P-glycoprotein concentrations appear to vary with menstrual cycle suggesting it may affect intracellular drug concentration of RAL in women.. Women will be enrolled in the study and followed during the course of a menstrual cycle while taking a dose of 400mg PO ...
The activity of P-glycoprotein (Pgp/MDR1/ABCB1) and multidrug resistance proteins (MRP/ABCC) influence the pharmacokinetics and bioavailability of many drugs. Few suitable cell lines for the study of drug transport exist. Additional non-human cell lines may help clarify species differences and contribute to the current knowledge of drug transport. The aim of the present study was to characterize three rat epithelial cell lines for transporter expression and activity. Transporter expression was assessed in intestinal IEC-6 and renal GERP and NRK-52E cells using RT-PCR and Western blot analysis. Pgp and Mrp transport activity were analyzed by measuring calcein accumulation and glutathione-S-bimane efflux, respectively. The three cell lines showed Pgp expression and Pgp-dependent transport, both decreasing with culture time after reaching confluency. Besides Pgp, cells expressed Mrp1, Mrp3, Mrp4, and Mrp5, while Mrp2 and Mrp6 were absent. In addition, they showed temperature- and Mrp-dependent ...
Supplementary Materialsmolecules-24-00707-s001. in a standard human being jejunum and were already validated for the testing of Axitinib tyrosianse inhibitor P-gp inducers and activators [5,21,26,27]. Open in a separate window Number 1 Chemical constructions of the oxygenated xanthones OX 1C6 investigated in this study. Additionally, using everted intestinal sacs of Wistar-Han rats, the effect of the most promising compound on P-gp activity was evaluated < 0.01; **** < 0.0001 vs. control (0 M)]. 2.4. Evaluation of P-Glycoprotein Transport Activity P-gp activity was evaluated using two different protocols: The first approach, by evaluating the accumulation of Rhodamine 123 (Rho 123) in the presence of the OXs (20.0 M) during the 60-min accumulation phase of the fluorescent P-gp substrate (Figure 4); and the second approach, by evaluating the accumulation of Rho 123 after pre-exposure of Caco-2 cells to the OXs (20.0 M) for 24 h (Figure 5). The first assay aims to evaluate the potential immediate ...
CUL4A encodes a core component of a cullin-based E3 ubiquitin ligase complex that regulates many critical processes such as cell cycle progression, DNA replication, DNA repair and chromatin remodeling by targeting a variety of proteins for ubiquitination and degradation. In the research described in this report we aimed to clarify whether CUL4A participates in multiple drug resistance (MDR) in breast cancer cells. We first transfected vectors carrying CUL4A and specific shCUL4A into breast cancer cells and corresponding Adr cells respectively. Using reverse transcription polymerase chain reactions and western blots, we found that overexpression of CUL4A in MCF7 and MDA-MB-468 cells up-regulated MDR1/P-gp expression on both the transcription and protein levels, which conferred multidrug resistance to P-gp substrate drugs, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. On the other hand, silencing CUL4A in MCF7/Adr and MDA-MB-468/Adr cells led to the opposite
5416 The proteasome inhibitor bortezomib has been approved for single-agent treatment of multiple myeloma and is being evaluated in other malignancies. Two prominent effects of bortezomib are inhibition of nuclear factor-kappa-B activation and stabilization of p53, both of which may affect the cellular response to cytotoxic drugs. The purpose of the present study was to assess efficacy of bortezomib in acute myeloid leukemia (AML) by determining its activity as a single agent in AML cell lines with wt (ML-1) and inactive (HL60) p53 and against cells overexpressing MDR proteins prevalent in AML, including P-glycoprotein (Pgp), multidrug resistance protein-1 (MRP-1), breast cancer resistance protein (BCRP) and lung resistance protein (LRP). In addition, interactions between bortezomib and chemotherapy drugs with activity in AML were studied. Cells were cultured for four days in 96-well microculture assays with bortezomib and the chemotherapy drugs Ara-C, DNR, Dox or Ida individually, ...
TY - JOUR. T1 - Generation of multidrug resistant lymphoma cell lines stably expressing P-glycoprotein. AU - Pop, Iliodora. AU - Pop, Laurentiu. AU - Vitetta, Ellen S.. AU - Ghetie, Maria Ana. PY - 2008/4/1. Y1 - 2008/4/1. N2 - The objective of this study was to generate new P-glycoprotein (P-gp)-expressing multidrug resistant (MDR) cell lines by drug selection. Since our previous studies have been carried out with cells infected with a P-gp-containing vector, it was important to confirm our findings in cells generated by drug selection. In this report, we describe three B-lymphoma cell lines which became drug-resistant by stepwise exposure to vincristine (VCR): Raji cells resistant to 18 nM VCR (R18V), Namalwa cells resistant to 21 nM VCR (N21V) and DHL-4 cells resistant to 12 nM VCR (DHL-41/12V). Cells overexpressed P-gp and continued to express CD19, CD20 and CD22, all of which are targets for monoclonal antibody (MAb) therapy. The P-gp pump in these new cells was functional as determiped by ...
Chitosan (CS), a nature-derived polysaccharide, is a promising nano-carrier material with good biocompatibility and biodegradability. However, the biomedical applications of CS are hindered because of its poor aqueous solubility. To circumvent this drawback, a series of Brij-grafted-chitosan copolymers (BCs) with various grafting degree of Brij-S20 were first developed and reported. The results indicated that the water solubility of BCs (from 9.13 to 9.54 mg/mL) were much higher than that of CS (0.32 mg/mL), due to the broken intra- and/or inter-molecular hydrogen bonds and the decreased initial crystallinity in BCs. The amphiphilic structure of BCs presented lower critical micelle concentration (0.116-0.376 mg/mL) thus facilitating its self-aggregation into micelles for drug encapsulation. Moreover, BCs markedly enhanced the intracellular uptake of rhodamine-123 in MDCK-MDR1 cells. This inhibition on Pgp-mediated efflux was also confirmed by confocal microscopy. In conclusion, BCs could be ...
The interactions between the human P-glycoprotein (Pgp) and two different types of immunosuppressant drugs known to modulate multidrug resistance in tumor cells have been directly investigated using our newly developed drug-stimulated ATPase assay for Pgp function. The macrolides FK506 and FK520 stimulate the Pgp-ATPase activity with affinities in the 100 nM range, nearly 10 times higher than that of verapamil, a well known Pgp substrate. On the other hand, the cyclic peptides cyclosporin A and dihydrocyclosporin C do not stimulate the Pgp-ATPase activity at all. They do, however, act as potent competitive inhibitors of verapamil-stimulated Pgp-ATPase activity, with affinity constants in the 20-25 nM range. Thus, although these two classes of immunosuppressant drugs affect the Pgp in different ways, they both probably interact with high affinity at the transported drug binding site(s) of the Pgp, which would explain their ability to resensitize multidrug-resistant cells to the killing action of ...
P-glycoprotein (P-gp) is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over-expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external) ...
Changes in P-glycoprotein and ABCG2 densities may play a role in amyloid-beta accumulation in Alzheimers disease. However, previous studies report conflicting results from different brain regions, without correcting for changes in vessel density. We developed an automated method to measure transporter density exclusively within the vascular space, thereby correcting for vessel density. We then examined variability in transporter density across brain regions, matter, and disease using two cohorts of post-mortem brains from Alzheimers disease patients and age-matched controls. Changes in transporter density were also investigated in capillaries near plaques and on the mRNA level. P-glycoprotein density varied with brain region and matter, whereas ABCG2 density varied with brain matter. In temporal cortex, P-glycoprotein density was 53% lower in Alzheimers disease samples than in controls, and was reduced by 35% in capillaries near plaque deposits within Alzheimers disease samples. ABCG2 ...
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Thiosemicarbazone-related compounds are well-known to have active antiviral, antibacterial, antimalarial, and antihypertensive properties (42), as well as antitumor activity that can overcome resistance to chemotherapeutics (19, 43). Recently, we reported that the small-molecule thiosemicarbazone NSC73306 is significantly more cytotoxic to cells that overexpress P-glycoprotein than to cells that do not, and this unique property is directly proportional to functional P-glycoprotein protein expression (19). Therefore, we proposed that NSC73306 could be used to resensitize P-glycoprotein-expressing multidrug resistant carcinoma cells to chemotherapy. However, in addition to P-glycoprotein, the presence of MRPs and ABCG2 is well documented in numerous types of the cancer cells (4) and has been shown to play a major role in the development of MDR in cancer cells (16, 18, 44, 45). For example, ABCG2 and MRP1 are known to transport numerous anticancer chemotherapeutics, whereas MRP4 and MRP5 can ...
TY - JOUR. T1 - Modulators of the multidrug-transporter, P-glycoprotein, exist in the human plasma. AU - Ichikawa, Misako. AU - Yoshimura, Akihiko. AU - Furukawa, Tatsuhiko. AU - Sumizawa, Tomoyuki. AU - Akiyama, Shin ichi. PY - 1990/1/15. Y1 - 1990/1/15. N2 - P-glycoprotein (P-gp) is thought to mediate the transport of anticancer drugs and to be responsible for the multidrug-resistant (MDR) phenotype. P-gp is also expressed in normal human tissues, such as the adrenal gland, kidney, liver, colon and capillary endothelium of the brain. However, the function and transporting substrates of P-gp in normal tissues are still not understood. This paper explains that some compounds in the human plasma can modulate the transporting activity of P-gp. A partially purified fraction from the human plasma enhanced the accumulation of anti-cancer agents in MDR cells. This fraction inhibited the efflux of vinblastine from MDR cells, and also inhibited the photoaffinity labeling of P-gp with azidopine as ...
P-glycoprotein belongs to the family of ATP-binding cassette proteins which hydrolyze ATP to catalyse the translocation of their substrates through membranes. This protein extrudes a large range of components out of cells, especially therapeutic agents causing a phenomenon known as multidrug resistance. Because of its clinical interest, its activity and transport function have been largely characterized by various biochemical studies. In the absence of a high-resolution structure of P-glycoprotein, homology modeling is a useful tool to help interpretation of experimental data and potentially guide experimental studies. We present here three-dimensional models of two different catalytic states of P-glycoprotein that were developed based on the crystal structures of two bacterial multidrug transporters. Our models are supported by a large body of biochemical data. Measured inter-residue distances correlate well with distances derived from cross-linking data. The nucleotide-free model features a large
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Dofequidar, also known as MS-209, is a quinolone-derived sphingomyelin synthase inhibitor that blocks P-glycoprotein and multidrug resistance-associated protein-1, is under development by Schering for the potential treatment of multidrug resistant tumors. Dofequidar was found to sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export.
TY - JOUR. T1 - P-glycoprotein retains function when reconstituted into a sphingolipid- and cholesterol-rich environment. AU - Modok, Szabolcs. AU - Heyward, Catherine. AU - Callaghan, Richard. PY - 2004/10/1. Y1 - 2004/10/1. N2 - P-glycoprotein (P-gp) appears to be associated within specialized raftlike membrane microdomains. The activity of P-gp is sensitive to its lipid environment, and a functional association hi raft microdomains will require that P-gp retains activity in the microenvironment. Purified hamster P-gp was reconstituted in liposomes comprising sphingomyelin and cholesterol, both highly enriched in membrane microdomains and known to impart a liquid-ordered phase to bilayers. The activity of P-gp was compared with that of proteoliposomes composed of crude egg phosphatidylcholine (unsaturated) or dipalmitoyl phosphatidylcholine (saturated) in the presence or absence of cholesterol. The maximal rate of ATP hydrolysis was not significantly altered by the nature of the lipid species. ...
BioAssay record AID 150617 submitted by ChEMBL: Concentration required for 50% inhibition (racemic) at binding site of human P-Glycoprotein (P-gp) in one-affinity model.
One of the plausible explanations for synergistic effects of silybin and anti-cancer drugs is inhibition of efflux function of dominant multidrug resistance (MDR) transporter P-glycoprotein [].. We have identified effective and relatively non-cytotoxic inhibitors of Pgp derived from 2,3-dehydrosilybin (2) (Fig. 1). Some of them were more effective inhibitors at lower concentrations than a standard Pgp efflux inhibitor cyclosporine A. Another group of 2,3-dehydrosilybin derivatives had also better inhibitory effects on Pgp efflux but a cytotoxicity was comparable with parent 2,3-dehydrosilybin. Structural requirements for improving inhibitory activity and reducing toxicity of 2,3-dehydrosilybin were established. Effect of E-ring substitution as well as an influence of the substituent size at the 7-OH position of A-ring on Pgp-inhibitory activity was evaluated for the first time in this study [].. ...
Patients with type 2 diabetes frequently have to be treated with more than one drug. Effects of oral antidiabetic drugs depend on the extent of drug absorption from the gut lumen, on metabolism of the drug in the liver, and on the extent of its excretion into bile and urine (21). In general, modification of all these processes by a second, concomitantly administered drug can alter the effects of oral antidiabetic drugs (21).. Recently, it was recognized that a broad variety of drugs, including many cardiovascular drugs such as statins and angiotensin II-receptor antagonists, is transported through biological membranes via specific transport proteins (15,22-24). For example, the efflux transporter P-glycoprotein, which translocates its substrates from the inside of the cell to the outside (e.g., from the hepatocyte into bile) is a major determinant of drug effects (1). If P-glycoprotein-mediated drug excretion is inhibited by a second, concomitantly administered compound, drug plasma ...
It is essential to establish a useful validation method for newly generated humanized mouse models. The novel approach of combining our established species-specific protein quantification method combined with in vivo functional studies is evaluated to validate a humanized mouse model of P-gp/MDR1 efflux transporter. The P-gp substrates digoxin, verapamil and docetaxel were administered to male FVB Mdr1a/1b(+/+) (FVB WT), FVB Mdr1a/1b(-/-) (Mdr1a/1b(-/-)), C57BL/6 Mdr1a/1b(+/+) (C57BL/6 WT) and humanized C57BL (hMDR1) mice. Brain-to-plasma total concentration ratios (K-p) were measured. Quantitative targeted absolute proteomic (QTAP) analysis was used to selectively quantify the protein expression levels of hMDR1, Mdr1a and Mdr1b in the isolated brain capillaries. The protein expressions of other transporters, receptors and claudin-5 were also quantified. The K-p for digoxin, verapamil, and docetaxel were 20, 30 and 4 times higher in the Mdr1a/1b(-/-) mice than in the FVB WT controls, as ...
Extra resources for Transporters as Drug Carriers: Structure, Function, Substrates (Methods and Principles in Medicinal Chemistry). Sample text. 3 Multidrug Resistance and ABC Transporters intracellular binding capacity > intracellular binding affinity > P-gp-mediated efflux [131, 151]. It is the conclusion of the above-mentioned authors that the delivery of paclitaxel to tumor cells rather than other mentioned factors determines intracellular drug concentration. This report was supported by a study that showed intravenous administration of radiolabeled daunorubicin to rats bearing bilateral tumors indicated that P-gp accounted only for partial drug resistance [152]. For both transporters, the NBDs (cytoplasmic side) are toward the bottom, while the periplasmic substrate binding subunits are uppermost. The ModBC structure (right) has a more open structure on the cytoplasmic side. The lower panels show a simplified representation of the MalG (left) and ModB (right) subunits in the same ...
Laniquidar is a third-generation P-gp inhibitor, which has been used in clinic trials for modulating multidrug resistance transporters. A study of docetaxel in combination with the new orally administered P-glycoprotein (P-gp) inhibitor R101933 showed that this combination was feasible. However, due to the low oral bioavailability of R101933 and high interpatient variability, no further attempts to increase the level of P-gp inhibition were made.
UIC 2 is a murine monoclonal antibody that recognises human P-glycoprotein (Pgp) on intact cell surfaces and inhibits Pgp-mediated efflux and the resistance of
They play a large role in the distribution and elimination of many clinically important therapeutic substances. Prescription and OTC drugs, foods and substances made by the body may be inhibitors and/or inducers of these transporters. Some drugs like cyclosporine are both substrates and inhibitors of P-gp (ABCB1), other drugs like nifedipine are inhibitors only and some drugs like digoxin are only substrates.. Since P-gps block absorption in the gut, they should be considered part of the "first-pass effect". In fact, they can "set up" or act as "gatekeepers" for later P450 cytochrome actions. If one drug is a substrate of both P-gp and CYP3A4 (both found in close proximity in the intestinal wall), and a second drug is added that is an inhibitor of both P-gp and CYP 3A4 (e.g., ketoconazole, erythromycin, mibefradil), then the first drug will be allowed in increased amounts. Since CYP3A4 is inhibited, levels of unmetabolized drug will enter the blood. The effect of P-gp blockade is to "open the ...
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ABC transmembrane transporters are involved in absorption, distribution and excretion of diverse drugs and xenobiotics. They are key factors in pharmacokinetics and in the elimination of toxic endogenous or exogenous compounds. Therefore, the aim of the present study was to investigate the influence of genetic polymorphisms of the best known member of this protein family, MDR1 (ABCB1). In addition, the identity of another ABC transporter assumed to be the major hepatocellular export pump for monoanionic bile acids should be revealed and characterized. MDR1 turned out as a highly polymorphic gene with many single nucleotide polymorphisms (SNPs). Most of the SNPs were intronic or silent. Homozygous carriers of the non-coding SNP in exon 26 3435C,T had lower intestinal P-glycoprotein expression rates and thus enhanced absorption of the model compound digoxin as compared to wildtype controls. The analysis of pharmacokinetic profiles in different MDR1-haplotypes of the linked SNPs in exon 21 2677 and ...
Multidrug resistance in human cells results from increased expression of the mdr1 (P-glycoprotein) gene. Although the same gene is activated in cells selected with different drugs, multidrug-resistant cell lines can be preferentially resistant to their selecting agent. The mdr1 cDNA sequence from vi …