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Biomedicine & Pharmacotherapy =... Aug 2021Cancer treatment is improving widely over time, but finding a proper defender to beat them seems like a distant dream. The quest for identification and discovery of... (Review)
Review
Cancer treatment is improving widely over time, but finding a proper defender to beat them seems like a distant dream. The quest for identification and discovery of drugs with an effective action is still a vital work. The role of a membrane protein called P-glycoprotein, which functions as garbage chute that efflux the waste, xenobiotics, and toxins out of the cancer cells acts as a major reason behind the therapeutic failure of most chemotherapeutic drugs. In this review, we mainly focused on a multiple strategies by employing 5-Fluorouracil, curcumin, and lipids in Nano formulation for the possible treatment of colorectal cancer and its metastasis. Eventually, multidrug resistance and angiogenesis can be altered and it would be helpful in colorectal cancer targeting.We have depicted the possible way for the depletion of colorectal cancer cells without disturbing the normal cells. The concept of focusing on multiple pathways for marking the colorectal cancer cells could help in activating one among the pathways if the other one fails. The activity of the 5-Fluorouracil can be enhanced with the help of curcumin which acts as a chemosensitizer, chemotherapeutic agent, and even for altering the resistance. As we eat to survive, so do the cancer cells. The cancer cells utilize the energy source to stay alive and survive. Fatty acids can be used as the energy source and this concept can be employed for targeting the colorectal cancer cells and also for altering the resistant part.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Curcumin; Drug Synergism; Fluorouracil; Humans; Lipids; Nanoparticles; Prodrugs
PubMed: 34082400
DOI: 10.1016/j.biopha.2021.111704 -
Pharmaceutical Biology Dec 2019Bajijiasu (BJJS), a main bioactive compound from Morinda officinalis F.C. How. (Rubiaceae), is widely administered concomitantly with other drugs for treating male...
CONTEXT
Bajijiasu (BJJS), a main bioactive compound from Morinda officinalis F.C. How. (Rubiaceae), is widely administered concomitantly with other drugs for treating male impotence, female infertility, fatigue, chronic rheumatism, depression, etc. Objective: This study investigates the regulation of P-glycoprotein (P-gp) by BJJS in vitro and in vivo.
MATERIAL AND METHODS
HepG2 cells were incubated with BJJS (10, 20 or 40 μM) for 48 h. C57 mice were orally treated with BJJS (25, 50 or 100 mg/kg) for 2 weeks. The protein and mRNA levels of P-gp were measured by using Western blot and real-time PCR, respectively. siNrf2 RNA was used to explore the mediation effects of Nrf2 on the P-gp expression. The efflux activity of P-gp was tested via a flow cytometry.
RESULTS
Incubation of HepG2 cells with BJJS at 10, 20, and 40 μM up-regulated the P-gp protein expression by 12.3%, 82.9%, and 134.3%, respectively. Treatment of C57 mice with BJJS at 25, 50 and 100 mg/kg increased the P-gp protein expression by 49.3%, 75.8% and 106.0%, respectively. Incubation of the cells with BJJS at 10, 20 and 40 μM up-regulated the total Nrf2 protein levels by 34.3%, 93.1% and 118.6%, respectively, and also increased the nuclear Nrf2 protein levels by 14.8%, 44.4% and 59.25%, respectively. The total Nrf2 protein levels were increased by 46.3%, 66.5%, and 87.4%, respectively, in the mice exposed to BJJS at 25, 50, and 100 mg/kg. Inhibition of Nrf2 by siRNA diminished the P-gp induction by 25.0%, 33.4%, and 38.7%, respectively, in the cells. In addition, BJJS enhanced the efflux activity of P-gp by 9.6%, 37.1%, and 48.1%, respectively, in the cells.
CONCLUSIONS
BJJS activates Nrf2 to induce P-gp expression, and enhanced the efflux activity of P-gp. The possibility of potential herb-drug interactions when BJJS is co-administered with other P-gp substrate drugs should be carefully monitored.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Cell Survival; Disaccharides; Doxorubicin; Hep G2 Cells; Humans; Kelch-Like ECH-Associated Protein 1; Male; Mice; Mice, Inbred C57BL; Morinda; NF-E2-Related Factor 2; Phytochemicals; RNA, Messenger; RNA, Small Interfering; Random Allocation; Signal Transduction
PubMed: 30929555
DOI: 10.1080/13880209.2019.1582679 -
Microbiome Sep 2021P-glycoprotein (P-gp) plays a critical role in protection of the intestinal epithelia by mediating efflux of drugs/xenobiotics from the intestinal mucosa into the gut...
BACKGROUND
P-glycoprotein (P-gp) plays a critical role in protection of the intestinal epithelia by mediating efflux of drugs/xenobiotics from the intestinal mucosa into the gut lumen. Recent studies bring to light that P-gp also confers a critical link in communication between intestinal mucosal barrier function and the innate immune system. Yet, despite knowledge for over 10 years that P-gp plays a central role in gastrointestinal homeostasis, the precise molecular mechanism that controls its functional expression and regulation remains unclear. Here, we assessed how the intestinal microbiome drives P-gp expression and function.
RESULTS
We have identified a "functional core" microbiome of the intestinal gut community, specifically genera within the Clostridia and Bacilli classes, that is necessary and sufficient for P-gp induction in the intestinal epithelium in mouse models. Metagenomic analysis of this core microbial community revealed that short-chain fatty acid and secondary bile acid production positively associate with P-gp expression. We have further shown these two classes of microbiota-derived metabolites synergistically upregulate P-gp expression and function in vitro and in vivo. Moreover, in patients suffering from ulcerative colitis (UC), we find diminished P-gp expression coupled to the reduction of epithelial-derived anti-inflammatory endocannabinoids and luminal content (e.g., microbes or their metabolites) with a reduced capability to induce P-gp expression.
CONCLUSION
Overall, by means of both in vitro and in vivo studies as well as human subject sample analysis, we identify a mechanistic link between cooperative functional outputs of the complex microbial community and modulation of P-gp, an epithelial component, that functions to suppress overactive inflammation to maintain intestinal homeostasis. Hence, our data support a new cross-talk paradigm in microbiome regulation of mucosal inflammation. Video abstract.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Gastrointestinal Microbiome; Homeostasis; Humans; Intestinal Mucosa; Mice
PubMed: 34493329
DOI: 10.1186/s40168-021-01137-3 -
Journal of Controlled Release :... Sep 2022P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two efflux transporters which are expressed in the apical (i.e. airway lumen-facing) membranes of...
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two efflux transporters which are expressed in the apical (i.e. airway lumen-facing) membranes of lung epithelial cells. To assess the influence of P-gp and BCRP on the pulmonary disposition of inhaled drugs, we performed positron emission tomography (PET) imaging in rats after intratracheal aerosolization of two model P-gp/BCRP substrate radiotracers (i.e. [C]erlotinib and [C]tariquidar). We studied rat groups in which both transporters were active (i.e. wild-type rats), either of the two transporters was inactive (Abcb1a/b and Abcg2 rats) or both transporters were inactive (Abcg2 rats in which pulmonary P-gp activity was inhibited by treatment with unlabeled tariquidar). PET-measured lung distribution data were compared with brain-to-plasma radioactivity concentration ratios measured in a gamma counter at the end of the PET scan. For [C]erlotinib, lung exposure (AUC) was moderately but not significantly increased in Abcb1a/b rats (1.6-fold) and Abcg2 rats (1.5-fold), and markedly (3.6-fold, p < 0.0001) increased in tariquidar-treated Abcg2 rats, compared to wild-type rats. Similarly, the brain uptake of [C]erlotinib was substantially (4.5-fold, p < 0.0001) increased when both P-gp and BCRP activities were impaired. For [C]tariquidar, differences in AUC between groups pointed into a similar direction as for [C]erlotinib, but were less pronounced and lacked statistical significance. Our study demonstrates functional P-gp and BCRP activity in vivo in the lungs and further suggests functional redundancy between P-gp and BCRP in limiting the pulmonary uptake of a model P-gp/BCRP substrate, analogous to the blood-brain barrier. Our results suggest that pulmonary efflux transporters are important for the efficacy and safety of inhaled drugs and that their modulation may be exploited in order to improve the pharmacokinetic and pharmacodynamic performance of pulmonary delivered drugs.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Animals; Blood-Brain Barrier; Brain; Erlotinib Hydrochloride; Lung; Neoplasm Proteins; Positron-Emission Tomography; Rats
PubMed: 35798092
DOI: 10.1016/j.jconrel.2022.06.065 -
Investigational New Drugs Aug 2023Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring MET...
Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring MET exon 14 skipping alterations. The aims of this work were to investigate the potential for drug-drug interactions via cytochrome P450 (CYP) 3A4/5 or P-glycoprotein (P-gp) inhibition. In vitro studies were conducted in human liver microsomes, human hepatocyte cultures and Caco-2 cell monolayers to investigate whether tepotinib or its major metabolite (MSC2571109A) inhibited or induced CYP3A4/5 or inhibited P-gp. Two clinical studies were conducted to investigate the effect of multiple dose tepotinib (500 mg once daily orally) on the single dose pharmacokinetics of a sensitive CYP3A4 substrate (midazolam 7.5 mg orally) and a P-gp substrate (dabigatran etexilate 75 mg orally) in healthy participants. Tepotinib and MSC2571109A showed little evidence of direct or time-dependent CYP3A4/5 inhibition (IC > 15 μM) in vitro, although MSC2571109A did show mechanism-based CYP3A4/5 inhibition. Tepotinib did not induce CYP3A4/5 activity in vitro, although both tepotinib and MSC2571109A increased CYP3A4 mRNA. In clinical studies, tepotinib had no effect on the pharmacokinetics of midazolam or its metabolite 1'-hydroxymidazolam. Tepotinib increased dabigatran maximum concentration and area under the curve extrapolated to infinity by 38% and 51%, respectively. These changes were not considered to be clinically relevant. Tepotinib was considered safe and well tolerated in both studies. The potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the clinical dose is considered low. Study 1 (midazolam): NCT03628339 (registered 14 August 2018). Study 2 (dabigatran): NCT03492437 (registered 10 April 2018).
Topics: Humans; Cytochrome P-450 CYP3A; ATP Binding Cassette Transporter, Subfamily B, Member 1; Midazolam; Cytochrome P-450 Enzyme System; Dabigatran; Caco-2 Cells; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; ATP Binding Cassette Transporter, Subfamily B; Drug Interactions
PubMed: 37415001
DOI: 10.1007/s10637-023-01378-z -
ELife Jan 2024P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance and...
P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance and mediates the bioavailability and pharmacokinetics of many drugs (Juliano and Ling, 1976; Ueda et al., 1986; Sharom, 2011). Decades of structural and biochemical studies have provided insights into how Pgp binds diverse compounds (Loo and Clarke, 2000; Loo et al., 2009; Aller et al., 2009; Alam et al., 2019; Nosol et al., 2020; Chufan et al., 2015), but how they are translocated through the membrane has remained elusive. Here, we covalently attached a cyclic substrate to discrete sites of Pgp and determined multiple complex structures in inward- and outward-facing states by cryoEM. In conjunction with molecular dynamics simulations, our structures trace the substrate passage across the membrane and identify conformational changes in transmembrane helix 1 (TM1) as regulators of substrate transport. In mid-transport conformations, TM1 breaks at glycine 72. Mutation of this residue significantly impairs drug transport of Pgp in vivo, corroborating the importance of its regulatory role. Importantly, our data suggest that the cyclic substrate can exit Pgp without the requirement of a wide-open outward-facing conformation, diverting from the common efflux model for Pgp and other ABC exporters. The substrate transport mechanism of Pgp revealed here pinpoints critical targets for future drug discovery studies of this medically relevant system.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B; Translocation, Genetic; ATP-Binding Cassette Transporters; Mutation
PubMed: 38259172
DOI: 10.7554/eLife.90174 -
Neuropsychopharmacology : Official... Apr 2023Mu opioid receptor (MOR) agonists comprise the most effective analgesics, but their therapeutic utility is limited by adverse effects. One approach for limiting such...
Mu opioid receptor (MOR) agonists comprise the most effective analgesics, but their therapeutic utility is limited by adverse effects. One approach for limiting such effects has been to develop "biased" MOR agonists that show preference for activating G protein over β-Arrestin signaling. However, the notion of biased agonism has been challenged by recent studies. Oliceridine (Olinvyk, TRV-130, OLC) is a selective MOR agonist approved by the FDA in 2020 for pain management in controlled clinical settings. Oliceridine purportedly demonstrates diminished adverse effects compared to morphine or other MOR agonists, a profile attributed to its biased agonism. However, recent studies suggest that oliceridine does not display biased agonism but instead weak intrinsic efficacy for G protein and β-Arrestin activation. Nevertheless, these insights have been derived from in vitro studies. To better understand oliceridine's in vivo efficacy profile, we performed a comprehensive assessment of its in vitro and in vivo pharmacology using both cultured cells and rodents. In vitro, oliceridine displayed high MOR affinity and weak intrinsic efficacy. In vivo, oliceridine showed impaired brain penetrance and rapid clearance, effects we attributed to its interaction with the P-glycoprotein (P-gp) efflux transporter. Moreover, we found that P-gp was essential for oliceridine's in vivo efficacy and adverse effect profiles. Taken together with prior studies, our results suggest that oliceridine's in vivo efficacy and adverse effect profiles are not attributed solely to its weak intrinsic efficacy or biased agonism but, to a large extent, its interaction with P-gp as well.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Analgesics, Opioid; GTP-Binding Proteins; ATP Binding Cassette Transporter, Subfamily B; beta-Arrestins; Receptors, Opioid, mu
PubMed: 36434081
DOI: 10.1038/s41386-022-01507-x -
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 -
FEBS Letters Dec 2020Small molecule transporters (SMTs) in the ABC and SLC families are important players in disposition of diverse endo- and xenobiotics. Interactions of environmental... (Review)
Review
Small molecule transporters (SMTs) in the ABC and SLC families are important players in disposition of diverse endo- and xenobiotics. Interactions of environmental chemicals with these transporters were first postulated in the 1990s, and since validated in numerous in vitro and in vivo scenarios. Recent results on the co-crystal structure of ABCB1 with the flame-retardant BDE-100 demonstrate that a diverse range of man-made and natural toxic molecules, hereafter termed transporter-interfering chemicals (TICs), can directly bind to SMTs and interfere with their function. TIC-binding modes mimic those of substrates, inhibitors, modulators, inducers, and possibly stimulants through direct and allosteric mechanisms. Similarly, the effects could directly or indirectly agonize, antagonize or perhaps even prime the SMT system to alter transport function. Importantly, TICs are distinguished from drugs and pharmaceuticals that interact with transporters in that exposure is unintended and inherently variant. Here, we review the molecular mechanisms of environmental chemical interaction with SMTs, the methodological considerations for their evaluation, and the future directions for TIC discovery.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Adenosine Triphosphatases; Amino Acid Sequence; Animals; Humans; Solute Carrier Proteins
PubMed: 33222203
DOI: 10.1002/1873-3468.14005 -
International Journal of Molecular... Jun 2023Multidrug resistance (MDR) is a common phenomenon in clinical oncology, whereby cancer cells become resistant to chemotherapeutic drugs A common MDR mechanism is the...
Multidrug resistance (MDR) is a common phenomenon in clinical oncology, whereby cancer cells become resistant to chemotherapeutic drugs A common MDR mechanism is the overexpression of ATP-binding cassette efflux transporters in cancer cells, with P-glycoprotein (P-gp) being one of them. New 3,4-seco-lupane triterpenoids, and the products of their intramolecular cyclization with the removed 4,4-gem-dimethyl group, were synthesized by the selective transformations of the A-ring of dihydrobetulin. Among the semi-synthetic derivatives, the MT-assay-enabled methyl ketone (), exhibiting the highest cytotoxicity (0.7-16.6 µM) against nine human cancer cell lines, including P-gp overexpressing subclone HBL-100/Dox, is identified. In silico, has been classified as a potential P-gp-inhibitor; however, the Rhodamine 123 efflux test, and the combined use of P-gp-inhibitor verapamil with in vitro, showed the latter to be neither an inhibitor nor a substrate of P-gp. As the studies have shown, the cytotoxic effect of against HBL-100/Dox cells is, arguably, induced through the activation of the ROS-mediated mitochondrial pathway, as evidenced by the positive Annexin V-FITC staining of apoptotic cells, the cell cycle arrest in the G0/G1 phase, mitochondrial dysfunction, cytochrome release, and the activation of caspase-9 and -3.
Topics: Humans; Doxorubicin; Drug Resistance, Neoplasm; Antineoplastic Agents; Drug Resistance, Multiple; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Transporters; Cell Line, Tumor
PubMed: 37373011
DOI: 10.3390/ijms24129863