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Current Medical Science Apr 2020D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is a pharmaceutical excipient approved by Chinese NMPA and FDA of USA. It's widely applied as a multifunctional... (Review)
Review
D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is a pharmaceutical excipient approved by Chinese NMPA and FDA of USA. It's widely applied as a multifunctional drug carrier for nanomedicine. The advantages of TPGS include P-glycoprotein (P-gp) inhibition, penetration promotion, apoptosis induction via mitochondrial-associated apoptotic pathways, multidrug resistant (MDR) reversion, metastasis inhibition and so on. TPGS-based drug delivery systems which are responding to external stimulus can combine the inhibitory functions of TPGS towards P-gp with the environmentally responsive controlled release property and thus exerts a synergistic anti-cancer effect, through increased intracellular drug concentration in tumors cells and well-controlled drug release behavior. In this review, TPGS-based nano-sized delivery systems responsive to different stimuli were summarized and discussed, including pH-responsive, redoxresponsive and multi-responsive systems in various formulations. The achievements, mechanisms and different characteristics of TPGS-based stimuli-responsive drug-delivery systems in tumor therapy were also outlined.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Drug Carriers; Drug Resistance, Neoplasm; Drug Synergism; Humans; Nanoparticles; Neoplasms; Vitamin E
PubMed: 32337683
DOI: 10.1007/s11596-020-2185-1 -
Molecules (Basel, Switzerland) Apr 2020A new series of -bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids...
A new series of -bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the efflux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a -bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds and showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp/CA XII inhibition in MDR cancer cells.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Biological Transport; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Stability; Humans; K562 Cells; Molecular Structure; Structure-Activity Relationship
PubMed: 32290281
DOI: 10.3390/molecules25071748 -
FEBS Letters Feb 2022A promising strategy to overcome multidrug resistance is the use of inhibitors of ABC drug transporters. For this reason, we evaluated the polyoxovanadates (POVs) [V O ]...
A promising strategy to overcome multidrug resistance is the use of inhibitors of ABC drug transporters. For this reason, we evaluated the polyoxovanadates (POVs) [V O ] (V ), [H V O (PO )] (V ), [V O Cl] (V ) and [V O I] (V ) as inhibitors of three major multidrug resistance-linked ABC transporters: P-glycoprotein (P-gp), ABCG2 and MRP1. All of the POVs selectively inhibited P-gp. V and V were the two most promising compounds, with IC values of transport inhibition of 25.4 and 22.7 µm, respectively. Both compounds inhibited P-gp ATPase activity, with the same IC value of 1.26 µm. V and V triggered different conformational changes in the P-gp protein with time-dependent inhibition, which was confirmed using the synthesized salt of V with rhodamine B, RhoB-V . The hydrophilic nature of POVs supports the hypothesis that these compounds target an unusual ligand-binding site, opening new possibilities in the development of potent modulators of ABC transporters.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1
PubMed: 34939198
DOI: 10.1002/1873-3468.14265 -
Journal of Medicinal Chemistry Oct 2021The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we...
The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, . effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Cell Line; Cell Line, Tumor; Drug Discovery; Drug Resistance, Multiple; HEK293 Cells; Humans; Mice; Molecular Docking Simulation; Quinazolines; Structure-Activity Relationship; Subcellular Fractions; Xenograft Model Antitumor Assays
PubMed: 34546748
DOI: 10.1021/acs.jmedchem.1c01452 -
Colloids and Surfaces. B, Biointerfaces Sep 2021Currently, multidrug resistance (MDR) is one of the major reasons for failure in clinical cancer chemotherapy. Overexpression of the ATP binding cassette (ABC)... (Review)
Review
Currently, multidrug resistance (MDR) is one of the major reasons for failure in clinical cancer chemotherapy. Overexpression of the ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which significantly increases the efflux of anticancer drugs from tumor cells, enhances MDR. In the past few decades, four generations of P-gp inhibitors have appeared. However, they are limited in clinical application due to their severe toxic side effects. As a P-gp inhibitor and carrier for loading chemotherapy agents, TPGS has received increasing attention due to its advantages and unique properties of reversing MDR. TPGS is an amphipathic agent that increases the solubility of most chemotherapy drugs and decreases severe side effects. In addition, TPGS is an excellent carrier with P-gp-inhibiting ability. In this review, we summarize the latest articles on TPGS-based nanodelivery systems to prevent MDR.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Polyethylene Glycols; Succinates; Vitamin E; alpha-Tocopherol
PubMed: 34130211
DOI: 10.1016/j.colsurfb.2021.111914 -
International Journal of Molecular... Jun 2020The ABCB1 transporter also known as P-glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette super-family of transporters; it is a...
The ABCB1 transporter also known as P-glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette super-family of transporters; it is a xenobiotic efflux pump that limits intracellular drug accumulation by pumping the compounds out of cells. P-gp contributes to a decrease of toxicity and possesses broad substrate specificity. It is involved in the failure of numerous anticancer and antiviral chemotherapies due to the multidrug resistance (MDR) phenomenon, where it removes the chemotherapeutics out of the targeted cells. Understanding the details of the ligand-P-gp interaction is therefore crucial for the development of drugs that might overcome the MRD phenomenon and for obtaining a more effective prediction of the toxicity of certain compounds. In this work, an in silico modeling was performed using homology modeling and molecular docking methods with the aim of better understanding the ligand-P-gp interactions. Based on different mouse P-gp structural templates from the PDB repository, a 3D model of the human P-gp (P-gp) was constructed by means of protein homology modeling. The homology model was then used to perform molecular docking calculations on a set of thirteen compounds, including some well-known compounds that interact with P-gp as substrates, inhibitors, or both. The sum of ranking differences (SRD) was employed for the comparison of the different scoring functions used in the docking calculations. A consensus-ranking scheme was employed for the selection of the top-ranked pose for each docked ligand. The docking results showed that a high number of π interactions, mainly π-sigma, π-alkyl, and π-π type of interactions, together with the simultaneous presence of hydrogen bond interactions contribute to the stability of the ligand-protein complex in the binding site. It was also observed that some interacting residues in P-gp are the same when compared to those observed in a co-crystallized ligand (PBDE-100) with mouse P-gp (PDB ID: 4XWK). Our in silico approach is consistent with available experimental results regarding P-gp efflux transport assay; therefore it could be useful in the prediction of the role of new compounds in systemic toxicity.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Binding Sites; Density Functional Theory; Drug Discovery; Hydrogen Bonding; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Reproducibility of Results; Structure-Activity Relationship
PubMed: 32517082
DOI: 10.3390/ijms21114058 -
Epilepsia Open Aug 2022The multidrug-resistance (MDR) phenotype is typically observed in patients with refractory epilepsy (RE) whose seizures are not controlled despite receiving several... (Review)
Review
The multidrug-resistance (MDR) phenotype is typically observed in patients with refractory epilepsy (RE) whose seizures are not controlled despite receiving several combinations of more than two antiseizure medications (ASMs) directed against different ion channels or neurotransmitter receptors. Since the use of bromide in 1860, more than 20 ASMs have been developed; however, historically ~30% of cases of RE with MDR phenotype remains unchanged. Irrespective of metabolic biotransformation, the biodistribution of ASMs and their metabolites depends on the functional expression of some ATP-binding cassette transporters (ABC-t) in different organs, such as the blood-brain barrier (BBB), bowel, liver, and kidney, among others. ABC-t, such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP-1), and breast cancer-resistance protein (BCRP), are mainly expressed in excretory organs and play a critical role in the pharmacokinetics (PK) of all drugs. The transporter hypothesis can explain pharmacoresistance to a broad spectrum of ASMs, even when administered simultaneously. Since ABC-t expression can be induced by hypoxia, inflammation, or seizures, a high frequency of uncontrolled seizures increases the risk of RE. These stimuli can induce ABC-t expression in excretory organs and in previously non-expressing (electrically responsive) cells, such as neurons or cardiomyocytes. In this regard, an alternative mechanism to the classical pumping function of P-gp indicates that P-gp activity can also produce a significant reduction in resting membrane potential (ΔΨ0 = -60 to -10 mV). P-gp expression in neurons and cardiomyocytes can produce membrane depolarization and participate in epileptogenesis, heart failure, and sudden unexpected death in epilepsy. On this basis, ABC-t play a peripheral role in controlling the PK of ASMs and their access to the brain and act at a central level, favoring neuronal depolarization by mechanisms independent of ion channels or neurotransmitters that current ASMs cannot control.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Epilepsy; Humans; Neoplasm Proteins; Seizures; Tissue Distribution
PubMed: 34542938
DOI: 10.1002/epi4.12537 -
Journal of Biomolecular Structure &... 2022The multidrug transporter P-glycoprotein is an ATP binding cassette (ABC) exporter responsible for resistance to tumor cells during chemotherapy. This study was designed...
The multidrug transporter P-glycoprotein is an ATP binding cassette (ABC) exporter responsible for resistance to tumor cells during chemotherapy. This study was designed with computational approaches aimed at identifying the best potent inhibitors of P-glycoprotein. Although many compounds have been suggested to inhibit P-glycoprotein, however, their information on bioavailability, selectivity, ADMET properties, and molecular interactions has not been revealed. Molecular docking, ADMET analysis, molecular dynamics, Principal component analysis (PCA), and binding free energy calculations were performed. Two compounds D1 and D2 showed the best docking score against P-glycoprotein and both compounds have 4-thiazolidinone derivatives containing indolin-3 one moiety are novel anti-tumor compounds. ADMET calculation analysis predicted D1 and D2 to have acceptable pharmacokinetic properties. The MD simulation discloses that D1-P-glycoprotein and D2-P-glycoprotein complexes are in stable conformation as apo-form. Hydrophobic amino acid such as phenylalanine plays significant on the interactions of inhibitors. Principal component analysis shows that both complexes are relatively similar variables as apo-form except planarity and Columbo energy profile. In addition, Quantitative Structural Activity Relationship (QSAR) of the ligand candidates were subjected to the principal component analysis (PCA) for pattern recognition. Partial-least-square (PLS) regression analysis was further utilized to model drug candidates' QSAR for subsequent prediction of the binding energy of validated drug candidates. PCA revealed groupings of the drug candidates based on the similarity or differences in drug candidates QSAR. Moreover, the developed PLS regression accurately predicted the values of the binding energy of drug candidates, with low residual error of prediction.Communicated by Ramaswamy H. Sarma.
Topics: Molecular Docking Simulation; Quantitative Structure-Activity Relationship; ATP Binding Cassette Transporter, Subfamily B, Member 1; Molecular Dynamics Simulation; Drug Resistance, Multiple
PubMed: 34060432
DOI: 10.1080/07391102.2021.1930159 -
Xenobiotica; the Fate of Foreign... May 2023(L.) DC, commonly used with florfenicol in Chinese veterinary clinics for respiratory tract infections, contains the major effective isoflavone, tectoridin (TEC). This...
(L.) DC, commonly used with florfenicol in Chinese veterinary clinics for respiratory tract infections, contains the major effective isoflavone, tectoridin (TEC). This study aimed to investigate the impact of TEC co-administration on the pharmacokinetics of florfenicol .Male rats received oral TEC (50 mg/kg BW) or sterile water for seven days, followed by a single oral dose of florfenicol (25 mg/kg BW) on the 8th day. Non-compartmental methods analysed the pharmacokinetics of florfenicol, while real-time reverse transcription polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analyses measured expression levels of cytochrome P450 (CYP) isoforms in the liver and P-glycoprotein (P-gp) in the jejunum.TEC significantly decreased florfenicol's AUC, MRT, , Vz/F, and by 24.75%, 18.43%, 55.47%, 43.05%, and 19.48%, while increasing CLz/F by 33.33%. TEC also up-regulated hepatic CYP1A2 and CYP3A1 mRNA expression, as well as intestinal MDR1, by 1.39-fold, 1.85-fold, and 1.65-fold. This coincided with a respective increase in protein expression by 1.37-fold, 1.39-fold, and 1.43-fold.These findings suggest that TEC-induced alterations in the pharmacokinetics of florfenicol may be attributed to increased CYP and P-gp expression. Further investigations are warranted to understand the implications of these findings on the clinical effectiveness of florfenicol in veterinary practice.
Topics: Rats; Male; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 Enzyme System; Isoflavones; Cytochrome P-450 CYP3A
PubMed: 37781957
DOI: 10.1080/00498254.2023.2261040 -
European Journal of Nuclear Medicine... Dec 2021P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[C]verapamil is...
PURPOSE
P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[C]verapamil is considered the gold standard tracer to measure the P-gp function; however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [F]MC225. This study compares the characteristics of (R)-[C]verapamil and [F]MC225 in the same subjects.
METHODS
Three non-human primates underwent 4 PET scans: 2 with (R)-[C]verapamil and 2 with [F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-Tissue Compartment Model (1-TCM) and metabolite-corrected plasma as input function. Tracer kinetic parameters at baseline and after inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed.
RESULTS
At baseline, [F]MC225 V values were higher, and k values were lower than those of (R)-[C]verapamil, whereas K values were not significantly different. After inhibition, V values of the 2 tracers were similar; however, (R)-[C]verapamil K and k values were higher than those of [F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K and V of both tracers.
CONCLUSION
[F]MC225 and (R)-[C]verapamil show comparable sensitivity to measure the P-gp function in non-human primates. Moreover, this study highlights the 30-min V as the best parameter to measure decreases in the P-gp function with both tracers. [F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline V.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Blood-Brain Barrier; Brain; Carbon Radioisotopes; Positron-Emission Tomography; Primates; Verapamil
PubMed: 34117508
DOI: 10.1007/s00259-021-05411-2