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Biomedicine & Pharmacotherapy =... Jul 2021P-glycoprotein, encoded by ATP-binding cassette transporters B1 gene (ABCB1), renders multidrug resistance (MDR) during cancer chemotherapy. Several synthetic small... (Review)
Review
P-glycoprotein, encoded by ATP-binding cassette transporters B1 gene (ABCB1), renders multidrug resistance (MDR) during cancer chemotherapy. Several synthetic small molecule inhibitors affect P-glycoprotein (P-gp) transport function in MDR tumor cells. However, inhibition of P-gp transport function adversely accumulates chemotherapeutic drugs in non-target normal tissues. Moreover, most small-molecule P-gp inhibitors failed in the clinical trials due to the low therapeutic window at the maximum tolerated dose. Therefore, downregulation of ABCB1-gene expression (P-gp) in tumor tissues seems to be a novel approach rather than inhibiting its transport function for the reversal of multidrug resistance (MDR). Several plant-derived phytochemicals modulate various signal transduction pathways and inhibit translocation of transcription factors, thereby reverses P-gp mediated MDR in tumor cells. Therefore, phytochemicals may be considered an alternative to synthetic small molecule P-gp inhibitors for the reversal of MDR in cancer cells. This review discussed the role of natural phytochemicals that modulate ABCB1 expression through various signal transduction pathways in MDR cancer cells. Therefore, modulating the cell signaling pathways by phytochemicals might play crucial roles in modulating ABCB1 gene expression and the reversal of MDR.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Resistance, Multiple; Gene Expression; Humans; Phytochemicals; Signal Transduction
PubMed: 34243600
DOI: 10.1016/j.biopha.2021.111632 -
World Journal of Gastroenterology Mar 2017The gastrointestinal barrier is constantly exposed to numerous environmental substrates that are foreign and potentially harmful. These xenobiotics can cause shifts in...
The gastrointestinal barrier is constantly exposed to numerous environmental substrates that are foreign and potentially harmful. These xenobiotics can cause shifts in the intestinal microbiota composition, affect mucosal immune responses, disturb tissue integrity and impair regeneration. The multidrug transporter p-glycoprotein (p-gp) plays a key role at the front line of host defence by efficiently protecting the gastrointestinal barrier from xenobiotic accumulation. This Editorial discusses how altered expression and function of p-gp may contribute to the development and persistence of chronic intestinal inflammation in inflammatory bowel diseases (IBD). Recent evidence implies multiple interactions between intestinal microbiota, innate immunity and xenobiotic metabolism p-gp. While decreased efflux activity may promote disease susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD. Mice deficient in MDR1A develop spontaneously chronic colitis, providing a highly valuable murine IBD model for the study of intestinal epithelial barrier function, immunoregulation, infectious co-triggers and novel therapeutic approaches. Possible associations of human gene polymorphisms with IBD susceptibility have been evaluated, but results are inconsistent. Future studies must focus on further elucidation of the pathophysiological relevance and immunological functions of p-gp and how its ambiguous effects could be therapeutically targeted in IBD.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Chronic Disease; Colitis; Drug Resistance, Multiple; Gastrointestinal Microbiome; Gene Expression Regulation; Homeostasis; Humans; Immunity, Innate; Inflammation; Inflammatory Bowel Diseases; Mice; Mice, Knockout; Polymorphism, Single Nucleotide; Xenobiotics
PubMed: 28321153
DOI: 10.3748/wjg.v23.i9.1513 -
International Journal of Oncology Nov 2023Multidrug resistance (MDR) seriously limits the clinical application of chemotherapy. A mechanism underlying MDR is the overexpression of efflux transporters associated... (Review)
Review
Multidrug resistance (MDR) seriously limits the clinical application of chemotherapy. A mechanism underlying MDR is the overexpression of efflux transporters associated with chemotherapeutic drugs. P‑glycoprotein (P‑gp) is an ATP‑binding cassette (ABC) transporter, which promotes MDR by pumping out chemotherapeutic drugs and reducing their intracellular concentration. To date, overexpression of P‑gp has been detected in various types of chemoresistant cancer and inhibiting P‑gp‑related MDR has been suggested. The present review summarizes the mechanisms underlying MDR mediated by P‑gp in different tumors and evaluated the related signaling pathways, with the aim of improving understanding of the current status of P‑gp‑mediated chemotherapeutic resistance. This review focuses on the main mechanisms of inhibiting P‑gp‑mediated MDR, with the aim of providing a reference for the study of reversing P‑gp‑mediated MDR. The first mechanism involves decreasing the efflux activity of P‑gp by altering its conformation or hindering P‑gp‑chemotherapeutic drug binding. The second inhibitory mechanism involves inhibiting P‑gp expression to reduce efflux. The third inhibitory mechanism involves knocking out the ABCB1 gene. Potential strategies that can inhibit P‑gp include certain natural products, synthetic compounds and biological techniques. It is important to screen lead compounds or candidate techniques for P‑gp inhibition, and to identify inhibitors by targeting the relevant signaling pathways to overcome P‑gp‑mediated MDR.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Transporters; Biological Products; Drug Resistance, Multiple
PubMed: 37654171
DOI: 10.3892/ijo.2023.5567 -
Clinical Pharmacokinetics Mar 2017Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and... (Review)
Review
Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20-50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration-time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug-drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Afatinib; Animals; Drug Interactions; ErbB Receptors; Humans; Kidney; Liver; Neoplasms; Protein Binding; Protein Kinase Inhibitors; Quinazolines; Radiation-Sensitizing Agents
PubMed: 27470518
DOI: 10.1007/s40262-016-0440-1 -
BioMed Research International 2015The efficient noninvasive treatment of neurodegenerative disorders is often constrained by reduced permeation of therapeutic agents into the central nervous system... (Review)
Review
The efficient noninvasive treatment of neurodegenerative disorders is often constrained by reduced permeation of therapeutic agents into the central nervous system (CNS). A vast majority of bioactive agents do not readily permeate into the brain tissue due to the existence of the blood-brain barrier (BBB) and the associated P-glycoprotein efflux transporter. The overexpression of the MDR1 P-glycoprotein has been related to the occurrence of multidrug resistance in CNS diseases. Various research outputs have focused on overcoming the P-glycoprotein drug efflux transporter, which mainly involve its inhibition or bypassing mechanisms. Studies into neurodegenerative disorders have shown that the P-glycoprotein efflux transporter plays a vital role in the progression of schizophrenia, with a noted increase in P-glycoprotein function among schizophrenic patients, thereby reducing therapeutic outcomes. In this review, we address the hypothesis that methods employed in overcoming P-glycoprotein in cancer and other disease states at the level of the BBB and intestine may be applied to schizophrenia drug delivery system design to improve clinical efficiency of drug therapies. In addition, the current review explores polymers and drug delivery systems capable of P-gp inhibition and modulation.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antipsychotic Agents; Blood-Brain Barrier; Drug Resistance; Humans; Schizophrenia
PubMed: 26491671
DOI: 10.1155/2015/484963 -
Proceedings. Biological Sciences May 2022Pesticides remain one of the most effective ways of controlling agricultural and public health insects, but much is still unknown regarding how these compounds reach...
Pesticides remain one of the most effective ways of controlling agricultural and public health insects, but much is still unknown regarding how these compounds reach their targets. Specifically, the role of ABC transporters in pesticide absorption and excretion is poorly understood, especially compared to the detailed knowledge about mammalian systems. Here, we present a comprehensive characterization of pesticide transporters in the model insect . An RNAi screen was performed, which knocked down individual ABCs in specific epithelial tissues and examined the subsequent changes in sensitivity to the pesticides spinosad and fipronil. This implicated a novel ABC drug transporter, in spinosad transport, but also highlighted the P-glycoprotein orthologue as the most impactful ABC in terms of chemoprotection. Further characterization of the P-glycoprotein family was performed via transgenic overexpression and immunolocalization, finding that and play enigmatic roles in pesticide toxicology perhaps determined by their different subcellular localizations within the midgut. Lastly, transgenic lines expressing P-glycoprotein from the major malaria vector were used to establish a system for characterization of this transporter in non-model insects. This study provides the basis for establishing as a model for toxicology research on drug transporters.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Animals; Animals, Genetically Modified; Anopheles; Drosophila melanogaster; Insecticide Resistance; Insecticides; Malaria; Mammals; Mosquito Vectors; Pesticides
PubMed: 35582794
DOI: 10.1098/rspb.2022.0625 -
Planta Medica Apr 2017This review summarizes published , animal, and clinical studies investigating the effects of green tea () extract and associated catechins on drug-metabolizing enzymes... (Review)
Review
This review summarizes published , animal, and clinical studies investigating the effects of green tea () extract and associated catechins on drug-metabolizing enzymes and drug transporters. studies suggest that green tea extract and its main catechin, (-)-epigallocatechin-3-gallate, to varying degrees, inhibit the activity of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. UGT1A1 and UGT1A4 isoforms were also inhibited by (-)-epigallocatechin-3-gallate. Animal studies suggest green tea extract and/or (-)-epigallocatechin-3-gallate significantly increase the bioavailability of diltazem, verapamil, tamoxifen simvastatin, 5-fluorouracil, and nicardipine. Conversely, green tea extract and/or (-)-epigallocatechin-3-gallate reduce the bioavailability of quetiapine, sunitinib, clozapine, and nadolol. Of the few clinical studies available for review, it appears neither green tea extract nor (-)-epigallocatechin-3-gallate inhibit any major cytochrome P450 enzyme. Regarding drug transporters, studies indicate P-glycoprotein, organic anion transporting polypeptide 1A1, organic anion transporting polypeptide 1B1, organic anion transporting polypeptide 1B3, organic anion transporting polypeptide 2B1, organic cation transporter 1, organic cation transporter 2, multidrug and toxin extrusion 1, and multidrug and toxin extrusion 2-K are potentially inhibited by green tea extract. A clinical study indicates the organic anion transporting polypeptide 1A1 transporter is inhibited by (-)-epigallocatechin-3-gallate while P-glycoprotein is unaffected. In conclusion, the ingestion of green tea extract or its associated catechins is not expected to result in clinically significant influences on major cytochrome P450 or uridine 5'-diphospho-glucuronosyltransferase enzyme substrates or drugs serving as substrates of P-glycoprotein. However, some caution is advised in the consumption of significant amounts of green tea beverages or green tea extract in patients prescribed known substrates of organic anion transporting polypeptide, particularly those with a narrow therapeutic index.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Availability; Biological Transport; Camellia sinensis; Catechin; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Organic Anion Transporters; Tea
PubMed: 28118673
DOI: 10.1055/s-0043-100934 -
International Journal of Molecular... Jan 2022Canine prostate cancer (PC) is an aggressive disease, and dogs can be considered comparative models for human PC. In recent years, canine PC has been shown to resemble...
Canine prostate cancer (PC) is an aggressive disease, and dogs can be considered comparative models for human PC. In recent years, canine PC has been shown to resemble human castrate-resistant prostate cancer. The influx and efflux of testosterone in prostatic luminal cells are regulated by P-glycoprotein (P-gp). Therefore, human PC generally lacks P-gp expression and maintains the expression of androgen receptors (ARs). However, this co-expression has not previously been investigated in dogs. Therefore, this study aimed to evaluate AR and P-gp co-expression to elucidate these protein patterns in canine prostate samples. We identified AR/P-gp double immunofluorescence co-expression of both proteins in normal luminal cells. However, in canine PC, cells lack AR expression and exhibit increased P-gp expression. These results were confirmed by gene expression analyses. Overall, our results strongly suggest that normal canine prostate testosterone influx may be regulated by P-gp expression, and that during progression to PC, prostatic cells lack AR expression and P-gp overexpress. P-gp expression in canine PC may be related to a phenotype of multiple drug resistance.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Androgens; Animals; Dogs; Gene Expression Regulation, Neoplastic; Male; Prostatic Neoplasms; Receptors, Androgen
PubMed: 35163087
DOI: 10.3390/ijms23031163 -
Biochimica Et Biophysica Acta.... Apr 2018ABC (ATP binding cassette) transporters, ubiquitous in all kingdoms of life, carry out essential substrate transport reactions across cell membranes. Their transmembrane... (Comparative Study)
Comparative Study Review
ABC (ATP binding cassette) transporters, ubiquitous in all kingdoms of life, carry out essential substrate transport reactions across cell membranes. Their transmembrane domains bind and translocate substrates and are connected to a pair of nucleotide binding domains, which bind and hydrolyze ATP to energize import or export of substrates. Over four decades of investigations into ABC transporters have revealed numerous details from atomic-level structural insights to their functional and physiological roles. Despite all these advances, a comprehensive understanding of the mechanistic principles of ABC transporter function remains elusive. The human multidrug resistance transporter ABCB1, also referred to as P-glycoprotein (P-gp), is one of the most intensively studied ABC exporters. Using ABCB1 as the reference point, we aim to compare the dominating mechanistic models of substrate transport and ATP hydrolysis for ABC exporters and to highlight the experimental and computational evidence in their support. In particular, we point out in silico studies that enhance and complement available biochemical data. "This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain."
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Adenosine Triphosphate; Animals; Biological Transport; Humans; Models, Biological; Molecular Dynamics Simulation; Protein Binding; Protein Conformation
PubMed: 29097275
DOI: 10.1016/j.bbamem.2017.10.028 -
Molecules (Basel, Switzerland) May 2019P-glycoprotein (P-gp) is a transmembrane protein that actively transports a wide variety of chemically diverse compounds out of the cell. It is highly associated with...
P-glycoprotein (P-gp) is a transmembrane protein that actively transports a wide variety of chemically diverse compounds out of the cell. It is highly associated with the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of drugs/drug candidates and contributes to decreasing toxicity by eliminating compounds from cells, thereby preventing intracellular accumulation. Therefore, in the drug discovery and toxicological assessment process it is advisable to pay attention to whether a compound under development could be transported by P-gp or not. In this study, an in silico multiclass classification model capable of predicting the probability of a compound to interact with P-gp was developed using a counter-propagation artificial neural network (CP ANN) based on a set of 2D molecular descriptors, as well as an extensive dataset of 2512 compounds (1178 P-gp inhibitors, 477 P-gp substrates and 857 P-gp non-active compounds). The model provided a good classification performance, producing non error rate (NER) values of 0.93 for the training set and 0.85 for the test set, while the average precision (AvPr) was 0.93 for the training set and 0.87 for the test set. An external validation set of 385 compounds was used to challenge the model's performance. On the external validation set the NER and AvPr values were 0.70 for both indices. We believe that this in silico classifier could be effectively used as a reliable virtual screening tool for identifying potential P-gp ligands.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Discovery; Humans; Mice; Models, Molecular; Models, Theoretical; Neural Networks, Computer
PubMed: 31130601
DOI: 10.3390/molecules24102006