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Fish Physiology and Biochemistry Oct 2022The role of the blood-brain barrier ATP-binding cassette protein transporter P-glycoprotein (P-gp) in protecting zebrafish (Danio rerio) from the central nervous system...
The role of the blood-brain barrier ATP-binding cassette protein transporter P-glycoprotein (P-gp) in protecting zebrafish (Danio rerio) from the central nervous system neurotoxicant ivermectin (IVM, 22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b) was examined in the absence and presence of the competitive inhibitor cyclosporin A (CsA). Zebrafish injected intraperitoneally with 1, 2, 5, or 10 µmol/kg IVM exhibited mortality 30 min following administration at the highest dose. At sublethal doses > 1 µmol/kg, IVM altered the swimming performance, exploratory behaviour, motor coordination, escape response and olfactory response in exposed fish. When fish were exposed to IVM in the presence of CsA, alterations in swimming and behaviours increased significantly and at the highest IVM/CsA ratio resulted in a complete lack of exploratory and olfactory behaviours. In separate experiments, fish were either fed or fasted, and the effects of IVM and CsA administration were examined. The effects of IVM administration and the exacerbated effects seen with CsA co-administration were not affected by fasting. This study provides evidence that P-gp provides a protective role in the BBB of fish against environmental neurotoxicants. The results also show that P-gp activity is maintained even under conditions of food deprivation, suggesting that this chemical defence system is prioritized over other energy expenditures during diet limitation.
Topics: Animals; Ivermectin; ATP Binding Cassette Transporter, Subfamily B, Member 1; Zebrafish; Cyclosporine; Fasting; ATP Binding Cassette Transporter, Subfamily B; Adenosine Triphosphate
PubMed: 36006557
DOI: 10.1007/s10695-022-01111-2 -
International Journal of Molecular... Feb 2023Acute myeloid leukemia (AML) remains an insidious neoplasm due to the percentage of patients who develop resistance to both classic chemotherapy and emerging drugs.... (Review)
Review
Acute myeloid leukemia (AML) remains an insidious neoplasm due to the percentage of patients who develop resistance to both classic chemotherapy and emerging drugs. Multidrug resistance (MDR) is a complex process determined by multiple mechanisms, and it is often caused by the overexpression of efflux pumps, the most important of which is P-glycoprotein (P-gp). This mini-review aims to examine the advantages of using natural substances as P-gp inhibitors, focusing on four molecules: phytol, curcumin, lupeol, and heptacosane, and their mechanism of action in AML.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Leukemia, Myeloid, Acute
PubMed: 36835550
DOI: 10.3390/ijms24044140 -
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 -
Expert Opinion on Therapeutic Patents Jun 2019P-glycoprotein is a complex ATP-ase transporter involved in physiological and pathological functions. In particular, it is involved in the onset of multidrug resistance... (Review)
Review
INTRODUCTION
P-glycoprotein is a complex ATP-ase transporter involved in physiological and pathological functions. In particular, it is involved in the onset of multidrug resistance in cancer, in ocular disease, Chronic Rhinosinusitis, CNS diseases such as Alzheimer, Parkinson, and epilepsy. One of the aims of clinicians and pharmacologists is to monitor P-gp activity through the inhibitors and to use its activity and/or expression in physiological barriers for the early diagnosis of several pathologies. Considering P-glycoprotein activity, several substrates have been characterized but the challenge is to design '' P-glycoprotein inhibitors.
AREAS COVERED
P-glycoprotein inhibitors display a large spectrum of activities. Here the contents of patents focused on the role of P-glycoprotein inhibitor in modulating MDR in cancer, in bioavailability, in ocular disease and Chronic Rhinosinusitis are reported.
EXPERT OPINION
The use of P-glycoprotein inhibitor , or in coadministration with therapeutic agents, for ocular disease, and Chronic Rhinosinusitis is promising and could be suggested for additional trials. By contrast, the bioavailability of the coadministrated drugs, increased by P-glycoprotein inhibitor, deserves a wider discussion, in particular on the pharmacokinetic aspect of both P-glycoprotein inhibitor and the coadministered drug.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Biological Availability; Drug Design; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Patents as Topic
PubMed: 31079547
DOI: 10.1080/13543776.2019.1618273 -
Bioorganic Chemistry Feb 2024P-glycoprotein (P-gp) over-expression is a key factor in multi-drug resistance (MDR), which is a major factor in the failure of cancer treatment. P-gp inhibitors have... (Review)
Review
P-glycoprotein (P-gp) over-expression is a key factor in multi-drug resistance (MDR), which is a major factor in the failure of cancer treatment. P-gp inhibitors have been demonstrated to have powerful pharmacological properties and may be used as a therapeutic approach to overcome the MDR in cancer cells. Combining clinical investigations with biochemical and computational research may potentially lead to a clearer understanding of the pharmacological properties and the mechanisms of action of these P-gp inhibitors. The task of turning these discoveries into effective therapeutic candidates for a variety of malignancies, including resistant and metastatic kinds, falls on medicinal chemists. A variety of P-gp inhibitors with great potency, high selectivity, and minimal toxicity have been identified in recent years. The latest advances in drug design, characterization, structure-activity relationship (SAR) research, and modes of action of newly synthesized, powerful small molecules P-gp inhibitors over the previous ten years are highlighted in this review. P-gp transporter over-expression has been linked to MDR, therefore the development of P-gp inhibitors will expand our understanding of the processes and functions of P-gp-mediated drug efflux, which will be helpful for drug discovery and clinical cancer therapies.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Structure-Activity Relationship; Drug Resistance, Multiple; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B
PubMed: 38029569
DOI: 10.1016/j.bioorg.2023.106997 -
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 -
Expert Opinion on Drug Delivery Sep 2018P-glycoprotein 1 (P-gp) pumps out many foreign/toxic substances out of the cells, including intracellular drugs, causing multidrug resistance (MDR) and chemotherapy... (Review)
Review
INTRODUCTION
P-glycoprotein 1 (P-gp) pumps out many foreign/toxic substances out of the cells, including intracellular drugs, causing multidrug resistance (MDR) and chemotherapy failure. It remains quite a challenge to inhibit P-gp to combat MDR and improve cellular bioavailability since it requires efficient inhibitors along with adequate formulation strategy. Lately, nanocarriers are gaining much attention and form an attractive platform for delivering drugs into cells. Therefore, nanomaterials act as direct inhibitors of P-gp will be an attractive alternative to overcome MDR.
AREAS COVERED
This paper reviews the most recent advances on those nanomaterials that are currently in the developmental stage and has proven useful to treat P-gp involved MDR. Also, we emphasize those emerging multifunctional nanomaterials that can construct 'smart' carriers for both tumor targeting and P-gp inhibition. Furthermore, the mechanisms behind P-gp inhibition and the nanoformulation strategies for drug delivery are also discussed.
EXPERT OPINION
In light of these updated reports, this review here seeks to suggest an alternative for the chemoresistant cases, and also bring about new thoughts on tackling P-gp concerned drug delivery issues. New advances in nanomaterials with P-gp inhibition are expected to broaden nanopharmaceutics and traditional chemotherapy applications in the coming years.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Biological Availability; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Nanostructures; Neoplasms
PubMed: 30169976
DOI: 10.1080/17425247.2018.1517749 -
Journal of Medicinal Chemistry Jun 2018Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. P-glycoprotein (P-gp), a promiscuous drug efflux pump, has been extensively studied for... (Review)
Review
Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. P-glycoprotein (P-gp), a promiscuous drug efflux pump, has been extensively studied for its association with MDR due to overexpression in cancer cells. Several P-gp inhibitors or modulators have been investigated in clinical trials in hope of circumventing MDR, with only limited success. Alternative strategies are actively pursued, such as the modification of existing drugs, development of new drugs, or combination of novel drug delivery agents to evade P-gp-dependent efflux. Despite the importance and numerous studies, these efforts have mostly been undertaken without a priori knowledge of how drugs interact with P-gp at the molecular level. This review highlights and discusses progress toward and challenges impeding drug development for inhibiting or evading P-gp in the context of our improved understanding of the structural basis and mechanism of P-gp-mediated MDR.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Protein Conformation
PubMed: 29251920
DOI: 10.1021/acs.jmedchem.7b01457 -
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 -
Molecular Diversity Nov 2014The translational failure between preclinical animal models and clinical outcome has alarmed us to search for a new strategy in the treatment of Alzheimer's disease... (Review)
Review
The translational failure between preclinical animal models and clinical outcome has alarmed us to search for a new strategy in the treatment of Alzheimer's disease (AD). Interlink between Pregnane X Receptor (PXR) and P-glycoprotein (Pgp) at the blood brain barrier (BBB) has raised hope toward a new disease modifying therapy in AD. Pgp is a major efflux transporter for beta amyloid (Aβ) at human BBB. A literature survey reveals diminished expression of Pgp transporter at the BBB in AD patients. Pregnane X Receptor is a major transcriptional regulator of Pgp. Restoration of Pgp at the BBB enhances the elimination of the Aβ from brain alongside and inhibits the apical to basolateral movement of Aβ from the circulatory blood. This review concentrates on in vitro, in vivo, and in silico advancements on the study of the PXR in context to Pgp and discusses the substrate and inhibitor specificity between PXR and Pgp.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Alzheimer Disease; Animals; Disease Management; Humans; Inflammation; Models, Molecular; Molecular Targeted Therapy; Pregnane X Receptor; Protein Binding; Protein Conformation; Receptors, Steroid
PubMed: 25213397
DOI: 10.1007/s11030-014-9550-6