Academic literature on the topic 'ABCB1 inhibitors'
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Journal articles on the topic "ABCB1 inhibitors"
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Michaelis, Martin, Florian Rothweiler, Thomas Nerreter, Marijke Van Rikxoort, Mohsen Sharifi, Michael Wiese, Taravat Ghafourian, and Jindrich Cinatl. "Differential Effects of the Oncogenic BRAF Inhibitor PLX4032 (Vemurafenib) and its Progenitor PLX4720 on ABCB1 Function." Journal of Pharmacy & Pharmaceutical Sciences 17, no. 1 (April 6, 2014): 154. http://dx.doi.org/10.18433/j3tw24.
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PURPOSE: The clinically approved oncogenic BRAF inhibitor PLX4032 (vemurafenib) was shown to be a substrate of the ATP-binding cassette (ABC) transporter ABCB1. Here, we compared PLX4032 and its structurally closely related precursor compound PLX4720 for their interference with ABCB1 and the ABCB1-mediated compound transport using docking and cell culture experiments. METHODS: For the docking study of PLX4032 and PLX4720 with ABCB1, we analysed binding of both compounds to mouse Abcb1a and to human ABCB1 using a homology model of human ABCB1 based on the 3D structure of Abcb1a. Naturally ABCB1 expressing cells including V600E BRAF-mutated and BRAF wild-type melanoma cells and cells transduced with a lentiviral vector encoding for ABCB1 were used as cell culture models. ABCB1 expression and function were studied by the use of fluorescent and cytotoxic ABCB1 substrates in combination with ABCB1 inhibitors. RESULTS: Docking experiments predicted PLX4032 to interact stronger with ABCB1 than PLX4720. Experimental studies using different cellular models and structurally different ABCB1 substrates confirmed that PLX4032 interfered stronger with ABCB1 function than PLX4720. For example, PLX4032 (20µM) induced a 4-fold enhanced rhodamine 123 accumulation compared to PLX4720 (20µM) in ABCB1-transduced UKF-NB-3 cells and reduced the IC50 for the cytotoxic ABCB1 substrate vincristine in this model by 21-fold in contrast to a 9-fold decrease induced by PLX4720. CONCLUSIONS: PLX4032 exerted stronger effects on ABCB1-mediated drug transport than PLX4720. This indicates that small changes in a molecule can substantially modify its interaction with ABCB1, a promiscuous transporter that transports structurally different compounds.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.PURPOSE: The clinically approved oncogenic BRAF inhibitor PLX4032 (vemurafenib) was shown to be a substrate of the ATP-binding cassette (ABC) transporter ABCB1. Here, we compared PLX4032 and its structurally closely related precursor compound PLX4720 for their interference with ABCB1 and the ABCB1-mediated compound transport using docking and cell culture experiments. METHODS: For the docking study of PLX4032 and PLX4720 with ABCB1, we analysed binding of both compounds to mouse Abcb1a and to human ABCB1 using a homology model of human ABCB1 based on the 3D structure of Abcb1a. Naturally ABCB1 expressing cells including V600E BRAF-mutated and BRAF wild-type melanoma cells and cells transduced with a lentiviral vector encoding for ABCB1 were used as cell culture models. ABCB1 expression and function were studied by the use of fluorescent and cytotoxic ABCB1 substrates in combination with ABCB1 inhibitors. RESULTS: Docking experiments predicted PLX4032 to interact stronger with ABCB1 than PLX4720. Experimental studies using different cellular models and structurally different ABCB1 substrates confirmed that PLX4032 interfered stronger with ABCB1 function than PLX4720. For example, PLX4032 (20µM) induced a 4-fold enhanced rhodamine 123 accumulation compared to PLX4720 (20µM) in ABCB1-transduced UKF-NB-3 cells and reduced the IC50 for the cytotoxic ABCB1 substrate vincristine in this model by 21-fold in contrast to a 9-fold decrease induced by PLX4720. CONCLUSIONS: PLX4032 exerted stronger effects on ABCB1-mediated drug transport than PLX4720. This indicates that small changes in a molecule can substantially modify its interaction with ABCB1, a promiscuous transporter that transports structurally different compounds. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Michaelis, Martin, Yvonne Voges, Florian Rothweiler, Fabian Weipert, Amara Zia-Ahmad, Jaroslav Cinatl, Andreas von Deimling, et al. "Testing of the Survivin Suppressant YM155 in a Large Panel of Drug-Resistant Neuroblastoma Cell Lines." Cancers 12, no. 3 (March 2, 2020): 577. http://dx.doi.org/10.3390/cancers12030577.
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The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). Seventy seven (77) cell lines displayed YM155 IC50s in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, TP53-mutant cells were not generally less sensitive to YM155 than TP53 wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.
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Michaelis, Martin, Florian Rothweiler, Thomas Nerreter, Mohsen Sharifi, Taravat Ghafourian, and Jindrich Cinatl. "Karanjin interferes with ABCB1, ABCC1, and ABCG2." Journal of Pharmacy & Pharmaceutical Sciences 17, no. 1 (March 10, 2014): 92. http://dx.doi.org/10.18433/j3bw2s.
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PURPOSE: The prominent ATP-binding cassette (ABC) transporters ABCB1, ABCC1, and ABCG2 are involved in substance transport across physiological barriers and therefore in drug absorption, distribution, and elimination. They also mediate multi-drug resistance in cancer cells. Different flavonoids are known to interfere with different ABC transporters. Here, the effect of the furanoflavonol karanjin, a potential drug with antiglycaemic, gastroprotective, antifungal, and antibacterial effects, was investigated on ABCB1, ABCC1, and ABCG2-mediated drug transport in comparison to the flavonoids apigenin, genistein, and naringenin. METHODS: Cells expressing the relevant transporters (ABCB1: UKF-NB-3ABCB1, UKF-NB-3rVCR10; ABCC1: G62, PC-3rVCR20; ABCG2: UKF-NB-3ABCG2) were used in combination with specific fluorescent and cytotoxic ABC transporter substrates and ABC transporter inhibitors to study ABC transporter function. Moreover, the effects of the investigated flavonoids were determined on the ABC transporter ATPase activities. RESULTS: Karanjin interfered with drug efflux mediated by ABCB1, ABCC1, and ABCG2 and enhanced the ATPase activity of all three transporters. Moreover, karanjin exerted more pronounced effects than the control flavonoids apigenin, genistein, and naringenin on all three transporters. Most notably, karanjin interfered with ABCB1 at low concentrations being about 1µM. CONCLUSIONS: Taken together, these findings should be taken into account during further consideration of karanjin as a potential drug for different therapeutic indications. The effects on ABCB1, ABCC1, and ABCG2 may affect the pharmacokinetics of co-administered drugs. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.METHODS: Cells expressing the relevant transporters (ABCB1: UKF-NB-3ABCB1, UKF-NB-3rVCR10; ABCC1: G62, PC-3rVCR20; ABCG2: UKF-NB-3ABCG2) were used in combination with specific fluorescent and cytotoxic ABC transporter substrates and ABC transporter inhibitors to study ABC transporter function. Moreover, the effects of the investigated flavonoids were determined on the ABC transporter ATPase activities.RESULTS: Karanjin interfered with drug efflux mediated by ABCB1, ABCC1, and ABCG2 and enhanced the ATPase activity of all three transporters. Moreover, karanjin exerted more pronounced effects than the control flavonoids apigenin, genistein, and naringenin on all three transporters. Most notably, karanjin interfered with ABCB1 at low concentrations being about 1µM.CONCLUSIONS: Taken together, these findings should be taken into account during further consideration of karanjin as a potential drug for different therapeutic indications. The effects on ABCB1, ABCC1, and ABCG2 may affect the pharmacokinetics of co-administered drugs.
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Yin, Wei, Jianfeng Xu, and Yanjiao Mao. "Synergistic effects of autophagy inhibitors combined with cisplatin against cisplatin-resistant nasopharyngeal cancer cells." Biochemistry and Cell Biology 99, no. 3 (June 2021): 322–29. http://dx.doi.org/10.1139/bcb-2020-0283.
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This study explored the synergistic effects of autophagy inhibitors combined with cisplatin against cisplatin-resistant nasopharyngeal cancer cells by treating HNE-1 and cisplatin (diamminedichloroplatinum; DDP)-resistant HNE1/DDP nasopharyngeal cancer cell lines with DDP, autophagy inhibitors, or a combination of autophagy inhibitors and DDP. Cell viability was determined via MTT (colorimetric) and colony-forming assays, and the rate of apoptosis was determined using propidium iodide (PI) and annexin V double-staining. The expressions of proteins were determined by Western blotting. For our in-vivo studies, a murine xenograft model was established to evaluate the anti-tumor effects of the combination of autophagy inhibitor and DDP. The results showed that treatment with DDP increased the expressions of ATP-binding cassette sub-family B member 1 (ABCB1), ATP Binding Cassette Subfamily C Member 1 (ABCC1), and P-glycoprotein 1 (P-gp) in the HNE1/DDP cell lines. Treatment with chloroquine decreased the expression levels of ABCB1, ABCC1, and P-gp, and increased the formation of LC3-II and the expression levels of p62 in the HNE1/DDP cells. Additionally, the combination of autophagy inhibitors and DDP produced a synergistic effect on DDP-induced cell death and apoptosis. Furthermore, the combination of the autophagy inhibitor and DDP showed significant anti-tumor effects in the xenograft mouse model. In summary, autophagy inhibitors show synergistic anti-tumor effects with DDP in vitro against DDP-resistant nasopharyngeal cancer cells and in vivo in our xenograft murine model.
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Ibrahim, Mahmoud A. A., Khlood A. A. Abdeljawaad, Alaa H. M. Abdelrahman, Laila A. Jaragh-Alhadad, Hesham Farouk Oraby, Eslam B. Elkaeed, Gamal A. H. Mekhemer, et al. "Exploring Natural Product Activity and Species Source Candidates for Hunting ABCB1 Transporter Inhibitors: An In Silico Drug Discovery Study." Molecules 27, no. 10 (May 12, 2022): 3104. http://dx.doi.org/10.3390/molecules27103104.
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The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ΔGbinding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.
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Natarajan, Karthika, Jasjeet Bhullar, Suneet Shukla, Mehmet Burcu, Suresh V. Ambudkar, and Maria R. Baer. "The Pim Kinase Inhibitor SGI-1776 Chemosensitizes Multidrug Resistant Cells by Both Inhibiting Drug Transport by ABCB1 and ABCG2 and Decreasing ABCB1 and ABCG2 Surface Expression On Cells That Overexpress Pim-1." Blood 120, no. 21 (November 16, 2012): 2462. http://dx.doi.org/10.1182/blood.v120.21.2462.2462.
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Abstract Abstract 2462 Overexpression of the ATP-binding cassette (ABC) cellular drug efflux proteins ABCB1 and ABCG2 on acute myeloid leukemia (AML) cells is associated with inferior chemotherapy outcomes. Nevertheless, inhibitors of drug transport have not improved treatment outcomes in clinical trials. The serine/threonine kinase Pim-1, encoded by a proto-oncogene originally identified as the proviral integration site in Moloney murine leukemia virus lymphomagenesis, is expressed in AML and is implicated in regulation of multiple key cellular processes, as well as drug resistance. Our group has shown that Pim-1 phosphorylates ABCB1 and ABCG2 and promotes their translocation to the cell surface, where they mediate drug efflux. The imidazo[1,2-b]pyridazine small molecule SGI-1776 (Tolero Pharmaceuticals, Inc. Salt Lake City, UT) is the first Pim kinase inhibitor to have entered clinical testing. SGI-1776 has been shown to sensitize ABCB1-overexpressing drug-resistant cells to ABCB1 substrate cancer chemotherapy drugs, but chemosensitization was found to be associated with direct inhibition of drug transport mediated by ABCB1. Moreover, while silencing of Pim-1 expression with siRNA was found to sensitize ABCG2-overexpressing cells to ABCG2 substrate chemotherapy drugs, the effects of SGI-1776 on resistance mediated by ABCG2 have not been studied. Therefore we studied the Pim-1-dependent and -independent effects of SGI-1776 on chemosensitivity of cells overexpressing ABCB1 and ABCG2. SGI-1776 at the Pim-1-inhibitory and non-cytotoxic concentration of 1 μM decreased the IC50s of ABCB1 and ABCG2 substrate drugs including daunorubicin and mitoxantrone 2- to 4-fold in leukemia and myeloma cell lines overexpressing ABCB1 and ABCG2, but had no effect on the IC50 of the non-substrate drug cytarabine, and no effect in parental cells. SGI-1776 also increased apoptosis of ABCB1- and ABCG2-overexpressing leukemia and myeloma cells exposed to ABCB1 and ABCG2 substrate chemotherapy drugs, respectively, and decreased their colony formation in the presence of substrate, but not non-substrate, chemotherapy drugs, with no effect on parental cells. We found that SGI-1776 decreased ABCB1 and ABCG2 surface expression, measured by flow cytometry, on K562/ABCB1 (p=0.013) and K562/ABCG2 (p=0.0038) leukemia cells, respectively, both of which express Pim-1 at high levels, without decrease in total cellular ABCB1 and ABCG2 expression, measured by Western blot analysis. In contrast, SGI-1776 had no effect on ABCB1 and ABCG2 surface expression on HL60/VCR leukemia and 8226/MR20 myeloma cells, which express ABCB1 and ABCG2, respectively, but express Pim-1 at lower levels. Thus SGI-1776 decreased ABCB1 and ABCG2 surface expression on cells that overexpress Pim-1, consistent with decreased cell surface translocation of ABCB1 and ABCG2 as a result of inhibition of Pim-1, but also chemosensitized cells expressing ABCB1 and ABCG2 in the absence of effects on ABCB1 and ABCG2 cell surface expression. We found that SGI-1776 indeed inhibited uptake of fluorescent substrates of both ABCB1 and ABCG2, measured by flow cytometry, in a concentration-dependent manner. We further determined that SGI-1776 inhibited ABCB1 and ABCG2 photoaffinity labeling with the transport substrate [125I]-IAAP and stimulated ABCB1 and ABCG2 ATPase activity, consistent with binding to drug-binding sites of ABCB1 and ABCG2 and inhibition of substrate transport by both proteins. Thus SGI-1776 both inhibits drug transport by ABCB1 and ABCG2 and decreases ABCB1 and ABCG2 surface expression on cells that overexpress Pim-1. Pim-1 is thought to be a clinically promising therapeutic target in AML and other malignancies, and other Pim kinase inhibitors are in preclinical and clinical development. Subsequent clinically applicable Pim kinase inhibitors should be characterized with regard to interactions with ABCB1 and ABCG2. In particular, while therapeutic strategies based on inhibition of drug transport mediated by ABCB1 with competitive inhibitors including PSC-833, zosuquidar and cyclosporin A have largely been clinically unsuccessful, inhibition of ABCB1 and ABCG2 cell surface translocation by Pim kinase inhibitors may have therapeutic implications. Disclosures: No relevant conflicts of interest to declare.
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Nosol, Kamil, Ksenija Romane, Rossitza N. Irobalieva, Amer Alam, Julia Kowal, Naoya Fujita, and Kaspar P. Locher. "Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1." Proceedings of the National Academy of Sciences 117, no. 42 (October 5, 2020): 26245–53. http://dx.doi.org/10.1073/pnas.2010264117.
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ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood. We determined cryo-EM structures of nanodisc-reconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. We found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that we termed the “access tunnel.” This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. Our structural data will also help the development of more potent and selective ABCB1 inhibitors.
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Winter, Stuart S., Debbie M. Lovato, Hadya M. Khawaja, Bruce S. Edwards, Irena D. Steele, Susan M. Young, Tudor I. Oprea, Larry A. Sklar, and Richard S. Larson. "Identification of Off-Patent Drugs That Reverse Daunorubicin Efflux Mediated by ABCB1 in T-ALL Cells." Blood 108, no. 11 (November 16, 2006): 2603. http://dx.doi.org/10.1182/blood.v108.11.2603.2603.
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Abstract In acute leukemias, the overexpression of P-glycoprotein, encoded by the ATP Binding Cassette B1 (ABCB1) gene contributes to multidrug resistance (MDR), and is considered one of the major obstacles to successful cancer chemotherapy. The identification of small molecules that reverse ABCB1 efflux activity is critical for the successful treatment of cancers, including relapsed T-lineage acute lymphoblastic leukemia (T-ALL). However, the dose-limiting toxicities of many MDR reversal agents have restricted their use in clinical trials, and more effective and clinically applicable reversal agents remain to be identified. We have recently developed a T-ALL cell line that overexpresses ABCB1 and exhibits multiple drug resistance (MDR) to daunorubicin, prednisolone, and vincristine, but not L-asparaginase. The MDR can be reversed by suppression of ABCB1 expresssion with siRNA or 5 μM cyclosporine (CSA). Using this cell line, we developed a flow cytometry based, high-throughput screening assay that quantifies ABCB1 efflux using the fluorescent probe JC-1 (Swerts, et al Leuk Lymphoma 45:2221–8, 2004). We screened a library of 880 off-patent drugs for their ability to inhibit ABCB1 efflux at concentrations of 4 μM, and 19 compounds were identified, including CSA. Based on a published record of safe internal use in humans, 12 compounds were retained for further analysis (3 compounds were originally described as calcium channel blockers, 1 as sodium channel blocker, 1 as ACE inhibitor, 1 as dopamine uptake inhibitor, 1 as Topoisomerase II inhibitor, 2 as steroids, 2 as antifungal and 1 as immunosuppressant). We determined the 50% inhibitory concentration (IC50) of drug for ABCB1 efflux, the efflux reversal concentration of drug that rescued DNR-induced T-ALL cell death (ECrev50), and the corresponding in vitro toxic dose in 50% of treated T-ALL cells (TD50). Due to space limitations, detailed data could not be presented in the abstract. To our knowledge, 8 of the 12 compounds have not been previously described as ABCB1 inhibitors. These compounds may be useful as chemosensitizers or as lead compounds for development of improved ABCB1 inhibitors in T-ALL as well as other cancers.
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Wang, Jingqiu, Dong-Hua Yang, Yuqi Yang, Jing-Quan Wang, Chao-Yun Cai, Zi-Ning Lei, Qiu-Xu Teng, Zhuo-Xun Wu, Linguo Zhao, and Zhe-Sheng Chen. "Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells." International Journal of Molecular Sciences 21, no. 4 (February 19, 2020): 1387. http://dx.doi.org/10.3390/ijms21041387.
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The overexpressing ABCB1 transporter is one of the key factors leading to multidrug resistance (MDR). Thus, many ABCB1 inhibitors have been found to be able to overcome ABCB1-mediated MDR. However, some inhibitors also work as a substrate of ABCB1, which indicates that in order to achieve an effective reversal dosage, a higher concentration is needed to overcome the pumped function of ABCB1, which may concurrently increase the toxicity. WYE-354 is an effective and specific mTOR (mammalian target of rapamycin) inhibitor, which recently has been reported to reverse ABCB1-mediated MDR. In the current study, 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cell viability and reversal effect of WYE-354 in parental and drug-resistant cells. Drug accumulation was performed to examine the effect of WYE-354 on the cellular accumulation of chemotherapeutic drugs. The ATPase (adenosine triphosphatase) activity of the ABCB1 transporter in the presence or absence of WYE-354 was conducted in order to determine the impact of WYE-354 on ATP hydrolysis. Western blot analysis and immunofluorescence assay were used to investigate the protein molecules related to MDR. In addition, the interaction between the WYE-354 and ABCB1 transporter was investigated via in silico analysis. We demonstrated that WYE-354 is a substrate of ABCB1, that the overexpression of the ABCB1 transporter decreases the efficacy of WYE-354, and that the resistant WYE-354 can be reversed by an ABCB1 inhibitor at a pharmacological achievable concentration. Furthermore, WYE-354 increased the intracellular accumulation of paclitaxel in the ABCB1-mediated MDR cell line, without affecting the corresponding parental cell line, which indicated that WYE-354 could compete with other chemotherapeutic drugs for the ABCB1 transporter substrate binding site. In addition, WYE-354 received a high score in the docking analysis, indicating a strong interaction between WYE-354 and the ABCB1 transporter. The results of the ATPase analysis showed that WYE-354 could stimulate ABCB1 ATPase activity. Treatment with WYE-354 did not affect the protein expression or subcellular localization of the ABCB1. This study provides evidence that WYE-354 is a substrate of the ABCB1 transporter, implicating that WYE-354 should be avoided for use in ABCB1-mediated MDR cancer.
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Dohse, Marius, Robert W. Robey, Cornelia Brendel, Susan Bates, Andreas Neubauer, and Christian Scharenberg. "Efflux of the Tyrosine Kinase Inhibitors Imatinib and Nilotinib (AMN107) Is Mediated by ABCB1 (MDR1)-Type P-Glycoprotein." Blood 108, no. 11 (November 16, 2006): 1367. http://dx.doi.org/10.1182/blood.v108.11.1367.1367.
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Abstract Chronic myeloid leukemia (CML) is a cancer affecting the hematopoietic stem cell (HSC) and is considered to be caused by the unregulated activity of the BCR-ABL tyrosine kinase. The development of tyrosine kinase inhibitors (TKIs) such as imatinib has revolutionized CML-therapy. However, resistance to imatinib has become a clinical reality and several potential mechanisms have been postulated to explain the imatinib resistance observed in CML cells. Among these, inherent protective mechanisms, such as overexpression of ATP-binding cassette (ABC) transporters, may lead to relapse or drug-resistance in CML patients receiving imatinib. Imatinib has previously been suggested to be a substrate for ABCB1, but conflicting data have been reported regarding this issue. However, whether the novel second-generation TKI nilotinib is a substrate for ABCB1 has not been investigated previously. Thus, we sought to characterize the interactions between ABCB1 and imatinib and nilotinib. We report that the TKIs imatinib and nilotinib show a reversible inhibition of ABCB1-mediated Rhodamine efflux in murine HSCs at clinically achieved concentrations. Imatinib abrogates Rhodamine efflux in HSC at 5 μM while nilotinib had a similar effect at a concentration of 0.2 μM. Additional studies with ABCB1-transfected HEK293 cells confirm nilotinib as a more potent inhibitor of ABCB1 than imatinib. Cytotoxicity studies using ABCB1-transfected HEK293 cells with Doxorubicine demonstrated inhibition of ABCB1-mediated efflux of Doxorubicine with increasing TKI concentration. In order to determine whether imatinib and nilotinib are in fact substrates and function not only as inhibitors of ABCB1, we performed experiments with various concentrations of radiolabeled imatinib and nilotinib. When ABCB1-transfected cells were incubated with 0.2 μM 14C-imatinib, intracellular concentrations were significantly lower compared to cells incubated with 14C-imatinib in the presence of different established ABCB1 inhibitors. However, transfected cells that were incubated in the presence of 14C-Imatinib at 1 μM or higher did not display reduced intracellular drug levels. In studies with the novel TKI nilotinib, ABCB1-expressing cells retained significantly less 14C-nilotinib compared to cells incubated with nilotinib in the presence of ABCB1 inhibitors, even at micromolar concentrations (33 % at 1 μM). However, similar to high concentrations with imatinib, the accumulation defect was not observed at supraphysiological concentrations of nilotinib. These experiments demonstrate both TKIs to be substrates for ABCB1 and indicate that TKI-efflux has a threshold and that TKIs at higher concentrations overwhelm the extrusion capacity of ABC transporters, offering an explanation for the conflicting reports as to whether TKIs are indeed substrates or only inhibitors. Since ABCB1 is known to be expressed on HSCs, we speculate that ABCB1 expression could mediate resistance in CML stem cells against imatinib and to the novel second-generation TKI nilotinib. Moreover, with ABCB1 being typically active at the Blood-Brain Barrier, decreased cerebrospinal levels of TKIs may have important clinical impact for the treatment of BCR-ABL positive B-ALL.
Dissertations / Theses on the topic "ABCB1 inhibitors"
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Ali, Wesam [Verfasser]. "Design and synthesis of novel ligands for Serotonin (5-HT6) receptor and inhibitors of ABCB1 Efflux pump / Wesam Ali." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2020. http://d-nb.info/1229916830/34.
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Arnaud, Ophélie. "Étude fonctionnelle de la région intracellulaire d’ABCG2 et modulation d’ABCG2 et ABCB1 humains par des petidomimétiques non compétitifs." Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10091/document.
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La surexpression de pompes d’efflux par les cellules cancéreuses permet l’élimination d’agents cytotoxiques, induisant alors une résistance à la chimiothérapie. Trois transporteurs ABC sont principalement impliqués dans cette résistance : ABCB1 (aussi appelé P-gp), ABCC1 (ou MRP1) et ABCG2 (ou BCRP, MXR, ABCP). Du fait de leur implication dans le phénotype de « MultiDrug Resistance », il est essentiel de mieux comprendre le fonctionnement de ces transporteurs. Une étude par mutagenèse dirigée a montré que les boucles intracellulaires, ICL0 et ICL1 sont impliquées dans le transport des substrats. Deux résidus sont particulièrement intéressants : W379 qui agirait comme un filtre des substrats ; et H457 qui participerait à la reconnaissance ou à la fixation des substrats. Par ailleurs, il est important de moduler cette chimiorésistance. Dans ce contexte nous avons développé une nouvelle classe d’inhibiteurs d’ABCB1 et ABCG2 non compétitifs basés sur un motif dipeptidique. Les composés les plus efficaces, CT1347 pour ABCB1 et CT1364 pour ABCG2, s’avèrent, d’une part peu ou pas cytotoxiques à fortes concentrations, abolissent d’autre part la résistance induite par ABCB1 ou ABCG2 et se comportent comme des inhibiteurs non compétitifs du Hoechst 33342 et de la daunorubicine. De plus, CT1364 inhibe l’activité ATPasique d’ABCG2 et induit une diminution rapide de l’expression de la protéine. Enfin, les 1ers tests in vivo de ce composé montrent que l’association avec l’irinotécan ralentit la croissance des xénogreffes de petite taille chez des sourisResistance to chemotherapy is partly due to efflux pumps expressed in the plasma membrane which prevent the accumulation of anticancer drugs in the tumour cells. Three human ATP-binding Cassette (ABC) transporters are particularly involved in this phenotype: P-gp/ABCB1, MRP1/ABCC1, and the last discovered BCRP/ABCG2. Because of their involvement in chemoresistance, it is critical to understand the mechanism by which those ABC transporters recognize and transport drugs. The mutagenesis study of the intracellular loops, ICL0 and 1 shows that these loops are involved in this mechanism. Two amino acids were particularly remarkable: W379 which act as a substrate filter and H457 which can be involved in substrate recognition and binding. In order to restore the cancer cell sensitivity to chemotherapeutic drugs, we have developed a new class of peptide inhibitors, specific to one transporter. A structure-activity relationship study has been performed and made it possible to develop a second generation of molecules. The most efficient compound inhibiting ABCB1 (CT1347) or ABCG2 (CT1364) have none or limitated cytotoxic effects. These compounds restore the activity of chemotherapeutic drugs and act as non competitive inhibitors. Moreover, CT1364 inhibits the ATP hydrolysis activity and lead to a rapid reduction of ABCG2 expression. Initial in vivo tests that have been carried out with CT1364 associated with irinotecan allow to observe a growth reduction of small mice xenografts
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Gassiot, Matthieu. "Rôle du récepteur des xénobiotiques PXR (Pregnane X Receptor) et de ses gènes cibles sur la sensibilité des lignées de cancer de prostate aux inhibiteurs de kinases." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT133/document.
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De plus en plus d’inhibiteurs de kinase (IKs) sont testés dans le cancer de la prostate qui représente chez l’homme un enjeu de santé publique majeur de par son incidence (1er cancer) et sa mortalité (4ème cancer). Les essais cliniques pour évaluer l'efficacité des IKs dans cette indication ont donné des résultats mitigés malgré la présence de leurs cibles pharmacologiques dans les tumeurs de prostate (VEGF, EGFR, CMET..), pouvant faire penser que l’inefficacité serait en partie liée à la molécule elle-même et à sa pharmacocinétique/pharmacodynamie. En effet, les IKs sont sujets à un métabolisme et un transport intense via des enzymes de phase I et II et des transporteurs contrôlés pour la majorité par le récepteur nucléaire PXR (Pregnane X Receptor, gène NR1I2). En plus d’être abondamment exprimé dans le foie et le long du tractus gastro-intestinal, PXR est également exprimé dans certaines tumeurs épithéliales et pourrait être impliqué dans la résistance aux chimiothérapies par augmentation du catabolisme et de l’efflux de ces agents anticancéreux. A ce jour une seule étude a révélé l’expression de PXR dans le cancer de la prostate sans en avoir évalué l’impact sur la réponse aux traitements utilisés dans cette indication. En collaboration avec le Pr G. Fromont, nous avons observé dans une cohorte de 449 patients que l’expression de PXR était plus fréquemment retrouvée dans les cancers résistants à la castration et les métastases, par rapport aux cancers cliniquement localisés dans lesquels l’expression de PXR était corrélée avec le stade TNM et le score ISUP. Ces résultats confirment donc l’intérêt d’étudier le rôle que peut jouer PXR et les gènes du métabolisme et du transport qu’il régule, dans la sensibilité aux IKs dans les cancers de la prostate.Nous avons mesuré l’expression de PXR et de ses gènes cibles dans les lignées de cancer de la prostate 22RV1, LnCap, PC3 et DU145. Les résultats montrent une expression significative des enzymes et transporteurs responsables de la détoxication des IKs mais une faible expression de PXR liée à des phénomènes d’hyperméthylation NR1I2 dans nos lignées Cela nous a conduit à établir des modèles de surexpression stable de PXR dans lesquels l’agoniste SR12813 est capable d’induire l’activité transcriptionnelle de ce xénorécepteur, indiquant la compétence métabolique de ces lignées. À l'aide de ces modèles, nous avons démontré que la surexpression de PXR module la réponse à l’erlotinib, le dasatinib, le dabrafénib et l’afatinib démontrant que PXR joue un rôle fonctionnel dans la sensibilité à ces IKs. Nous avons également démontré que certains inhibiteurs avaient des propriétés agonistes de PXR, notamment le dabrafénib qui montre un effet agoniste plus marqué que le composé de référence SR12813, ce qui n’a jamais été démontré. Cette découverte originale nous a conduit à engager une collaboration pour tenter de cristalliser le complexe PXR/dabrafénib et à tester l’hypothèse que l’induction de l’activité PXR pouvait entraîner une modification du métabolisme et/ou du transport d’autres médicaments co-administrés. Or, nous avons observé dans la lignée 22RV1 un effet additif entre le dabrafénib et le tramétinib, une combinaison approuvée dans le traitement du mélanome, qui devient antagoniste lorsque PXR est surexprimé, résultat qui va effectivement dans le sens de notre hypothèse même s’il reste à démontrer que cet effet est bien lié à une altération du métabolisme de ces IKs, ce que nous sommes en train d’évaluer en dosant les métabolites de ces IKs. L’ensemble de nos données pourraient servir de rationnel biologique dans le choix des IKs ou de leurs combinaisons à tester avec les hormonothérapies et chimiothérapies déjà utilisés dans le traitement du cancer de la prostate, afin de potentialiser la réponse tumoraleMore and more kinase inhibitors (KIs) are tested in prostate cancer that represents a major health issue in men with its incidence and mortality rates. Clinical trials to evaluate KIs efficacy in prostate cancer gave disapointing results depsite the presence of KIs pharmacological targets in prostate tumors (VEGF, EGFR, CMET..), suggesting that inefficiency of these drugs would be at least in part linked to the inhibitor itself or its pharmacodynamics/pharmacokinetics parameters. Indeed KIs are metabolized and transported via phase I and II enzymes that are mainly controlled by the xenoreceptor PXR (Pregnane X Receptor, gène NR1I2). It is mainly expressed in liver and gastro-intestinal tract but also in epithelial tumors. PXR is also involved in the resistance to chemotherapies by increasing the catabolism and the efflux of these anticancer agents. To date only one study evaluated PXR expression in prostate cancer without evaluating its impact on treatment efficacy. In collaboration with Pr G. Fromont we analyzed a cohort of 449 prostate tumors and observed that PXR was more frequently detected in castration resistant or metastatic tumors as compared to clinically localized forms in which PXR expression was significantly correlated with TNM and ISUP Score. These results confirmed the interest to study the potential role of PXR and its target genes in the sensitivity to kinase inhibitors in prostate cancer models.We measured the expression of PXR and its target genes in prostate cancer cell lines 22RV1, LnCap, PC3 and DU145. The results showed that enzymes and transporters involved in KI detoxification was significantly expressed in these cells whereasPXR was poorly expressed due to hypermethylation of NR1I2 in our cells. This lead us to develop specific prostate cancer cell models stably overexpressing PXR in which transcriptional activity of PXR can be induced by its known agonist SR12813 further indicating that prostate cancer cells are metabolically competent. Using these models we showed that PXR overexpression modulates the sensitivity of 22RV1 cells to erlotinib, dasatinib, dabrafenib and afatinib, demonstrating that PXR plays a functional role in the sensitivity to KIs. We also demonstrated that several KIs were PXR agonists, including dabrafenib that displayed enhanced agonistic properties as compared to SR12813, a result that was never published before. This original finding led us to engage the cristalization of PXR/dabrafenib complex and to test whether induction of PXR could lead to an alteration of metabolism and transport of other drugs that are co-administered. In this line we have observed that in 22RV1 cells the additive effect of the combination of dabrafenib with trametinib that is already approved in the treatment of melanomas, became antagonistic when PXR was overexpressed in these cells. This result is supporting our hypothesis though we still need to demonstrate that this effect is linked to a change in drugs metabolism, which is currently under investigation by the measurement of the known metabolites of these KIs.Altogether, our data could serve as rational basis for the choice of kinase inhibitors or their potential combinations that could be tested in further clinical trials alone or in association with hormone therapies or with chemotherapies that are currently prescribed in the treatment of advanced prostate cancers, in order to potentiate tumor response
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Gomes, Guilherme Wataru. "Expressão gênica dos transportadores de membrana ABCB1,ABCG2, SLC22A1 e SLCO1A2 em linhagens celulares tratadas com inibidor comercial da via JAK-STAT." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-16032016-095918/.
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INTRODUÇÃO: A desregulação da via de sinalização JAK-STAT é uma característica marcante das neoplasias mieloproliferativas (NMPs), doenças clonais da célula tronco hematopoética, dentre as quais encontra-se a mielofibrose (MF). Diversos inibidores de JAK foram desenvolvidos para o tratamento da MF e encontram-se em diferentes fases de desenvolvimento clínico. Devido ao seu desenvolvimento recente, pouco se sabe a respeito do papel de transportadores de membrana na farmacocinética desses compostos. Essas proteínas realizam o influxo e efluxo celular de substratos endógenos e xenobióticos, e alterações na expressão desses transportadores podem influenciar a resposta a esses fármacos. OBJETIVO: Avaliar o efeito de um inibidor comercial da via JAK-STAT na expressão gênica dos transportadores de membrana ABCB1, ABCG2, SLC22A1 e SLCO1A2 em células HepG2, Caco-2 e HEL92.1.7. MÉTODOS: Linhagens de carcinoma hepatocelular (HepG2), adenocarcinoma colorretal (Caco-2) e eritroleucemia humana homozigotas para JAK2V617F (HEL92.1.7) foram cultivadas e tratadas o inibidor comercial da via JAK-STAT JAK Inhibitor I. Para determinar a concentração ideal para o tratamento com o inibidor, as células foram tratadas com diversas concentrações do inibidor de JAK por 24 horas e foram feitos testes de viabilidade celular e fragmentação do DNA. Com as condições de tratamento padronizadas, foi extraído o RNA total das células e sintetizado o cDNA, para análise das expressões de RNAm dos genes ABCB1, ABCG2, SLC22A1 e SLCO1A2 por PCR em tempo real. Foi também avaliada a expressão dos transportadores de efluxo ABCB1 e ABCG2 por citometria de fluxo, utilizando anticorpos primários direcionados a essas proteínas. RESULTADOS: Nas células HepG2, foi observado um aumento da expressão de RNAm de ABCB1 nas células tratadas com 4,00 µM do inibidor de JAK, quando comparado com o controle (células incubadas apenas com o veículo) (P=0,041). Não foi observada alteração da expressão de RNAm de ABCG2 e SLC22A1 com o tratamento com o inibidor de JAK nessa linhagem (P>0,05); a expressão de RNAm de SLCO1A2 não foi detectada nessa linhagem. Nas células Caco-2, a expressão de ABCB1, ABCG2, SLC22A1 e SLCO1A2 não se alterou com o tratamento com o inibidor de JAK nas concentrações utilizadas (0,25 µM a 1,00 µM) por 24 horas (P>0,05). Para as células HEL92.1.7, não foi observada diferença na expressão de RNAm de ABCB1, ABCG2 e SLC22A1 com o tratamento com 1,00 µM do inibidor de JAK por 24 horas em comparação ao controle (P>0,05); nessa linhagem, a expressão de RNAm de SLCO1A2 não foi detectada. A expressão proteica dos transportadores ABCB1 e ABCG2 não sofreu alteração com o tratamento com o inibidor de JAK nas condições utilizadas nas três linhagens celulares estudadas (P>0,05). CONCLUSÕES: Apenas as células HepG2 apresentaram um aumento da expressão de RNAm do transportador de efluxo ABCB1 em concentrações elevadas do inibidor de JAK, sugerindo que os inibidores de JAK podem modular a expressão do gene desse transportador no fígado. O tratamento com o inibidor da via JAK-STAT não foi associado com alterações na expressão proteica de ABCB1 e ABCG2 em todas as células estudadas.BACKGROUND: JAK-STAT pathway signaling disregulation is a hallmark of myeloproliferative neoplasms (MPN), hematopoietic stem cell clonal diseases, among which is myelofibrosis (MF). Several JAK inhibitors have been developed for MF treatment and are found in different stages of clinical development. Because the recent development of these compounds, the role of drug transporters in their pharmacokinetics is poorly understood. These proteins perform celular influx and effux of endogenous substrates and xenobiotics, and changes in the expression of these drugs transporters may affect the response to these drugs. AIM: To evaluate the effect of a JAK-STAT pathway commercial inhibitor in gene expression of drug transporters ABCB1, ABCG2, SLC22A1 and SLCO1A2 in HepG2, Caco-2 and HEL92.1.7 cells. METHODS: Hepatocellular carcinoma cell line HepG2, colorectal adenocarcinoma cell line Caco-2 and human erythroleukemia homozygous JAK2V617F cell line HEL92.1.7 were grown and treated with the JAK-STAT pathway inhibitor JAK Inhibitor I. In order to determine the optimal concentration for treatment with the inhibitor, cells were treated with several concentrations of JAK inhibitor by 24 hours, and cell viability and DNA fragmentation tests were performed. Once the treatment conditions were standardized, total RNA were obtained from the cells, and cDNA was synthesized in order to evaluate the mRNA expression of ABCB1, ABCG2, SLC22A1 and SLCO1A2 genes, performed by real time PCR. We also evaluate the expression of drug efflux transporters ABCB1 and ABCG2 by flow cytometry, using primary antibodies directed to these proteins. RESULTS: In HepG2 cells, it was observed an increase in ABCB1 mRNA expression in cells treated with 4,00 µM of JAK inhibitor, when compared with controls (cells exposed only to the vehicle) (P=0.041). There was no change in ABCB2 and SLC22A1 mRNA expression with the treatment with JAK inhibitor in this cell line (P>0.05); SLCO1A2 mRNA was not detected in this cell line. In Caco-2 cells, ABCB1, ABCG2, SLC22A1 and SLCO1A2 mRNA expression did not change with treatment with the JAK inhibitor at the concentrations used (0.25 µM to 1.00 µM) by 24 hours (P>0.05). In HEL92.1.7 cells, it was not observed differences in ABCB1, ABCG2 and SLC22A1 mRNA expression with the treatment with 1 µM of JAK inhibitor by 24 hours when compared with controls (P>0.05); in this cell line, SLCO1A2 mRNA was not detected. Protein expression of ABCB1 and ABCG2 drug transporters has not changed with treatment with the JAK inhibitor under the conditions used in the three cell lines studied. CONCLUSIONS: Only HepG2 cells presented an increase in mRNA expression of drug efflux transporter ABCB1 in presence of high levels of JAK inhibitor, suggesting that JAK inhibitors could modulate this transporter gene expression in liver. Treatment with JAK-STAT pathway inhibitor was not associated with changes in ABCB1 and ABCG2 protein expression in all cell lines studied.
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Cusinato, Diego Alberto Ciscato. "Associação dos polimorfismos do CYP3A5 e da PGP com a farmacocinética do tacrolimus, nefrotoxicidade aguda e rejeição do enxerto após transplante renal." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/17/17133/tde-20082013-151121/.
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Tacrolimus (TAC) é um fármaco imunossupressor muito utilizado na prevenção de rejeição aguda após o transplante de órgãos. Essa droga apresenta um índice terapêutico muito baixo e grande variabilidade intra e interindividual, sendo necessário programas de monitorização terapêutica para se otimizar a eficácia e limitar a toxicidade. O TAC é um fármaco substrato do CYP3A5 e transportado pela proteína de efluxo PGP e acredita-se que o polimorfismos genéticos (SNPs) destas proteínas estejam relacionados a alta variabilidade farmacocinética desta droga. Neste estudo, investigamos a influência dos polimorfismos destas proteínas sobre alguns parâmetros farmacocinéticos do TAC e também, na incidência de lesões renais e rejeição em receptores de transplante renal. Pacientes recebendo TAC a no mínimo 12 meses (n=108) foram genotipados (PCR real time) para os polimorfismos do CYP3A5*3 (rs776746) e do gene ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582) e 3435C>T (rs1045642). Dados da concentração plasmática de vale (Co; ng/mL), dose diária normalizada (mg/dia por Kg do paciente) e a concentração plasmática do fármaco normalizada pela dose ingerida (Co/dose, ng/mL por mg/dia por kg do paciente) de TAC foram obtidos dos prontuários médicos ao longo de três anos após o transplante renal. O desfecho clínico foi analisado avaliando-se a curva de sobrevida o enxerto, a função renal obtida pelo clearance de creatinina (Equação de Cockroft-Gault), e desenvolvimento de lesões renais e rejeição aguda e crônica com diagnósticos estabelecidos mediante suspeita clínica e confirmados pela avaliação das biópsias quanto a presença de necrose tubular aguda (NTA) e nefropatia crônica do enxerto (NFC) de acordo com a classificação de BANFF 07. Os haplótipos do gene ABCB1 foram inferidos estatisticamente utilizando o software PHASE (version 2.1). Diferenças foram consideradas significativas quando p<0,05. Não observamos desvios em relação ao esperado pelo equilíbrio de Hardy-Weinberg em nossa população para nenhum dos genes estudados. Frequências alélicas destes polimorfismos (6986G 74%; 1236C 60%; 3435C 59% and 2677G 64%) e haplótipos (49% 2677G-3435C-1236C e 31% 2677T-3435T-1236T) foram consistentes com outros estudos realizados na população brasileira. Indivíduos portadores de ao menos um alelo *1 do gene CYP3A5 necessitavam de maiores doses de TAC para obter níveis plasmáticos semelhantes aos dos indivíduos homozigotos para o alelo *3 (0,09 ± 0,03 vs. 0,06 ± 0,03; mg/dia/kg; p<0,001). Ao final do primeiro ano de transplante pacientes CYP*3/*3 apresentavam praticamente o dobro da razão Co/dose quando comparados com os pacientes CYP*1/*1 (144,60 ± 67,29 vs. 70,44 ± 56,05 ng*mL-1 /mg*kg- 1 /dia; p<0,001). Observou-se semelhante em relação quando indivíduos portadores dos alelos e haplótipo variante da PGP foram avaliados. Não encontramos associações significativas entre os genótipos e a sobrevida do enxerto ou clearance de creatinina. No entanto, observamos que os pacientes portadores do haplótipo GCC apresentaram maior incidência de desenvolvimento de NFC. Este estudo confirma o efeito dos polimorfismos do CYP3A5 e, em menor grau da PGP na farmacocinética do TAC. No entanto, não encontramos associações entre esses polimorfismos e desfechos clínicos significantes, sugerindo que a genotipagem para o CYP3A5 ou ABCB1 ainda não deva ser incorporada na prática clínica como uma ferramenta para o manejo de transplante renal.Tacrolimus (TAC) is widely used to prevent acute rejection following solid-organ transplantation. This drug is characterized by a narrow therapeutic index and drug monitoring programs are required both to optimize efficacy and to limit toxicity. TAC is known to be substrate of cytochrome P450 (CYP) 3A5 and P-glycoprotein (PGP/ABCB) and its been suggested that genetic polymorphisms (SNPs) of these proteins are highly associated with variations in TAC pharmacokinetics. We investigated the influence of polymorphisms of CYP3A5 and ABCB1 gene on the pharmacokinetic parameters (PK) of TAC and on the incidence of kidney injuries and allograft rejection (AR) in renal transplant recipients. Patients receiving TAC for at least 12 months (n=108) were genotyped (real-time PCR) for CYP3A5*3 (rs776746) and for ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582) and 3435C>T (rs1045642) polymorphisms. TAC predose concentration (Co; ng/mL), TAC daily dose (mg/day per kg body weight) and dose-normalized predose concentrations (Co/dose; ng/mL per mg/day per kg body weight) were retrieved from medical records up to 03 years after transplantation. Clinical outcomes were analyzed evaluating renal function in terms of creatinine clearance ( Cockroft-Gault equation) and allograft survival. Kidney injuries and AR diagnostics were established by clinical suspicion and in presence of histological findings in renal biopsies according to the 2007 Banff classification. ABCB1 gene haplotypes were statistically inferred using PHASE software (version 2.1). No deviation from Hardy-Weinberg equilibrium was observed in our study population for the polymorphic loci examined in CYP3A5 and ABCB1. Allelic frequencies of these polymorphisms (6986G 74%; 1236C 60%; 3435C 60% and 2677G 65%) and haplotypes (49% 2677G-3435C-1236C and 30% 2677T- 3435T-1236T) were consistent with other studies in the Brazilian population. Individuals carrying at least one CYP3A5*1 allele required higher TAC dose to achieve similar TAC blood levels as the homozygous individuals for the *3 allele (0.09 ± 0.03 vs.0.06 ± 0.03, mg/day per kg body weight, p<0.001). The presence of the CYP3A5*1 allele was also associated with lower TAC Co/dose compared to CYP*3 homozygous (84.9 ± 43.2 vs. 144.6 ± 66.7 ng/mL per mg/day per kg body weight, p<0.001). Regarding ABCB1 polymorphisms, individuals homozygous for the variant allele of each individual SNP and for the haplotype (TTT) showed higher Co/dose ratio. No associations were found between SNPs or haplotypes and allograft survival or creatinine clearance. We did find, though, that patients carrying GCC haplotype had a higher incidence of chronic rejection. Our findings confirm the effect of CYP3A5 and, less pronounced of ABCB1 polymorphisms, on the TAC pharmacokinetic. On the other hand, we did not find any association between these polymorphisms and relevant clinical outcomes, suggesting that CYP3A5 and ABCB1 genotyping must not be incorporated as a useful clinical tool on the management of kidney transplantation.
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Arnaud, Ophélie. "Étude fonctionnelle de la région intracellulaire d'ABCG2 et modulation d'ABCG2 et ABCB1 humains par des petidomimétiques non compétitifs." Phd thesis, Université Claude Bernard - Lyon I, 2011. http://tel.archives-ouvertes.fr/tel-00846207.
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La surexpression de pompes d'efflux par les cellules cancéreuses permet l'élimination d'agents cytotoxiques, induisant alors une résistance à la chimiothérapie. Trois transporteurs ABC sont principalement impliqués dans cette résistance : ABCB1 (aussi appelé P-gp), ABCC1 (ou MRP1) et ABCG2 (ou BCRP, MXR, ABCP). Du fait de leur implication dans le phénotype de " MultiDrug Resistance ", il est essentiel de mieux comprendre le fonctionnement de ces transporteurs. Une étude par mutagenèse dirigée a montré que les boucles intracellulaires, ICL0 et ICL1 sont impliquées dans le transport des substrats. Deux résidus sont particulièrement intéressants : W379 qui agirait comme un filtre des substrats ; et H457 qui participerait à la reconnaissance ou à la fixation des substrats. Par ailleurs, il est important de moduler cette chimiorésistance. Dans ce contexte nous avons développé une nouvelle classe d'inhibiteurs d'ABCB1 et ABCG2 non compétitifs basés sur un motif dipeptidique. Les composés les plus efficaces, CT1347 pour ABCB1 et CT1364 pour ABCG2, s'avèrent, d'une part peu ou pas cytotoxiques à fortes concentrations, abolissent d'autre part la résistance induite par ABCB1 ou ABCG2 et se comportent comme des inhibiteurs non compétitifs du Hoechst 33342 et de la daunorubicine. De plus, CT1364 inhibe l'activité ATPasique d'ABCG2 et induit une diminution rapide de l'expression de la protéine. Enfin, les 1ers tests in vivo de ce composé montrent que l'association avec l'irinotécan ralentit la croissance des xénogreffes de petite taille chez des souris
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Tangella, Lokeswari Prathyusha. "An investigation on role of the ATP-binding cassette B5 (ABCB5) transporter as potential mediator of melanoma resistance to BRAF inhibition." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2020. https://ro.ecu.edu.au/theses/2369.
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Cutaneous melanoma is a highly metastatic and drug-resistant skin cancer type, responsible for a disproportionate number of skin cancer deaths. Targeted therapies, in the form of BRAF inhibitors (BRAFis), have been effective at treating BRAFV600 mutant melanomas. However, majority of the melanoma patients fail to respond to BRAFis due to intrinsic or acquired resistance within one year of treatment commencement. Multiple mechanisms that contribute to BRAFi resistance in melanoma cells have been identified, as discussed in the review in Chapter 1. Overexpression of ATP-binding cassette (ABC) transporters has been linked to multidrug resistance in numerous cancer types. These transporters expel the anti-cancer drugs out of the cell, thereby decreasing the intracellular concentration of the drug. In melanoma, the ATP-binding cassette B5 transporter (a member of ABC superfamily) has been linked to chemoresistance by drug extrusion. Moreover, overexpression of ABCB5 has been observed in BRAFV600 melanoma cells after short-term BRAFi treatment. In this study we investigated the role of the ABCB5 transporter as potential mediators of resistance to BRAFis by drug expulsion.
In Chapter 2, we showed increased ABCB5 expression in melanoma cell lines after short-term treatment with the BRAFis accompanied by an increased expression of melanocytic signature. Gene expression of fluorescent activated cell sorted melanoma cells into ABCB5high and ABCB5low populations, revealed an increased melanocytic signature in the ABCB5high population. Moreover, analysis of single-cell RNA sequencing (scRNAseq) data of two BRAFV600 melanoma cell lines, A2058 and 451Lu, revealed a strong association between ABCB5 expression and melanocytic signature. Based on these initial observations, the capacity of the ABCB5 transporter to efflux BRAFis was evaluated indirectly through an in-silico approach using molecular docking simulations (Chapter 3 and 4), and directly through in vitro experiments using an ABCB5 overexpressing melanoma BRAFV600 cell line (Chapter 5).
In Chapter 3, a full-length ABCB5 model was generated, based on mouse ATP-binding cassette B1 transporter (ABCB1; Pgp1), a close homologue of ABCB5. Molecular dynamics simulations were performed in 2 model cell membranes and the dominant conformation was identified. Docking simulations of known ABCB5 substrates such as taxanes, anthracyclines, camptothecin and etoposide enabled the identification of at least three putative substrate binding sites in ABCB5. The overlap of these three binding sites with validated binding sites for these chemotherapeutic drugs in Pgp1 corroborate our findings. In Chapter 4, docking simulations revealed at least one overlapping binding site for BRAFis and chemotherapeutic drugs on ABCB5, suggesting that BRAFis could potentially act as a substrate for ABCB5. In Chapter 5, we generated an ABCB5 overexpressing BRAFV600E melanoma cell line. However, no differences in sensitivity to BRAF inhibition was observed as a result of ABCB5 overexpression. Intracellular drug accumulation analyses revealed no reduction in vemurafenib or dabrafenib concentrations, indicating that BRAFis do not act as substrates for ABCB5.
Altogether, our studies suggest that ABCB5 expression is linked to the melanocytic program. However, despite the molecular docking evidence that BRAFis may be substrates of ABCB5, in vitro studies failed to demonstrate direct efflux of BRAFis by ABCB5.
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Repeľová, Beáta. "Studium vlivu antiretrovirálních léčiv na transmembránový transport tenofoviru disoproxil fumarátu přes monovrstvu MDCKII-ABCB1 buněk." Master's thesis, 2017. http://www.nusl.cz/ntk/nusl-371009.
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Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Beáta Repeľová Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Study of effects of antiretroviral drugs on transmembrane transport of tenofovir disoproxil fumarate across MDCKII - ABCB1 cell monolayer Tenofovir disoproxil fumarate (TDF) - ester prodrug of tenofovir is considered as one of the most frequently used component of combination antiretroviral therapy. Several ways of application and good patients' tolerability is typical for this compound. TDF is a substrate of dug transporter such as P-glycoprotein (P-gp) therefore its efflux activity may limit the bioavailability after oral administration and distribution of TDF. As many of antiretroviral drugs are also substrates or inhibitors of P-gp, drug - drug interactions with TDF at the level of transmembrane transport could be expected. The aim of the diploma thesis was to describe effects of co-administered antiretroviral drugs on transfer of TDF across MDCKII cell monolayer by using bidirectional transport and concentration equilibrium setups. The results of experiments confirmed that TDF is a substrate of P-gp. High values of efflux ratio describing transmembrane transport of TDF across parental cells have been observed. This...
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LI, HAI-CHEN, and 李海辰. "Synthesis of imidazole analogs as ABCB1/ABCG2 inhibitors and the study of their structure-activity relationship." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/18307404638521153952.
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碩士東海大學
化學系
104
During the treatment of cancer, multidrug resistance (MDR) is one of the most intractable problems. Multidrug resistance is often caused by the overexpression of ABC transporter (ATP-binding cassette transporter) ABCB1, ABCC1, ABCG2 which result in cancer drug to be exported out of the cell, rendering chemotherapy ineffective. As an effort to counteract this problem, we first took the substructure of tariquidar,2-benzamido-N-phenylbenzamide as the lead compound, and synthesize derivatives with different functional groups. While the synthesis of these derivatives were not as successful, we then synthesized compounds derived from three imidazole inhibitors screened at Professor Chung-Pu Wu’s laboratory, Chang Gung University. The ABC transporter protein inhibitory activity, showed that the nitrile substituting derivative demonstrated the best activity and when carboxyl group was esterified, the activity increased as well. The inhibitory activity of compounds showed that the hydrophobic group was preferred for ABCG2 inhibition. Neither electronic nor structure size of substituents appeared to affect the ABC transporter inhibition.
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Luo, Shi Yu, and 羅仕瑜. "Human ABCB1 (P-glycoprotein/MDR1) and ABCG2 (BCRP/MXR) Mediate Resistance to Polo-like kinase 1 inhibitors." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/48402034791397339617.
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碩士長庚大學
生物醫學研究所
102
The overexpression of the serine/threonine specific polo-like kinase 1 (Plk1) has been detected in various types of cancer, and thus has fast become an attractive therapeutic target for cancer therapy. Plk1 inhibitors BI 2536, volasertib and GSK461364, were designed to selectively inhibit cancer cell proliferation by promoting G2/M cell cycle arrest at nanomolar concentrations. Unfortunately, alike most chemotherapeutic agents, the development of acquired resistance to Plk1 inhibitors is prone to present a significant therapeutic challenge. One of the most common mechanisms for acquired resistance in cancer chemotherapy is associated with the overexpression of ATP-binding cassette (ABC) transporters ABCB1, ABCC1 and ABCG2. Here, we discovered that in human cancer cells, the overexpression of ABCB1 and/or ABCG2 can lead to acquired resistance to three selective Plk1 inhibitors, BI 2536, volasertib and GSK461364. Moreover, these Plk1 inhibitors stimulate the ATPase activity of ABCB1 and ABCG2, as well as competitively inhibit the drug substrate transport mediated by ABCB1 and ABCG2. More significantly, the reduced chemosensitivity and Plk1 inhibitors-mediated G2/M cell cycle arrest in cancer cells overexpressing either ABCB1 or ABCG2 can be significantly restored in the presence of selective inhibitor of ABCB1 and ABCG2. Taken together, our findings indicate that in order to circumvent ABCB1 or ABCG2-mediated acquired resistance to Plk1 inhibitors, a combined regimen of Plk1 inhibitors and modulators or clinically active drugs that potently inhibit the function of ABC drug transporters, should be considered as a potential treatment strategy in the clinic.
Conference papers on the topic "ABCB1 inhibitors"
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Ansbro, Megan R., Suneet Shukla, Suresh V. Ambudkar, Stuart H. Yuspa, and Luowei Li. "Abstract 5635: Development of a high-throughput cell and fluorescent image-based ABCB1-mediated efflux assay for screening inhibitors of ABCB1." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-5635.
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Barbuti, Anna Maria, Bhargav A. Patel, Tanaji T. Talele, and Zhe-Sheng Chen. "Abstract 2144: Next generation inhibitors to reverse ABCB1 transport mediated multidrug resistance in cancer." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-2144.
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Fan, Lin, Mark C. de Gooijer, Levi Buil, Nienke A. de Vries, Jos H. Beijnen, and Olaf van Tellingen. "Abstract LB-301: The impact of Abcb1 and Abcg2 on the brain penetration of PI3K-mTOR inhibitors." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-lb-301.
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Sodani, Kamlesh S., Amit K. Tiwari, Satyakam Singh, Atish Patel, Zhijie Xiao, Junjiang Chen, Yueli Sun, Tanaji T. Talele, and Zhe-Sheng Chen. "Abstract 777: GW583340 and GW2974, human EGFR and HER-2 inhibitors, reverse ABCG2- and ABCB1-mediated drug resistance." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-777.
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Wu, Chung-Pu, Hong-May Sim, and Suresh V. Ambudkar. "Abstract 766: Human ABCB1 and ABCG2 confer acquired resistance to Polo-like kinase 1 inhibitors, BI 2536, volasertib and GSK641364." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-766.
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Kwon, Woo Sun. "Abstract 5458: Identification of functional downstream gene of ABCB1 2677 G>T/A polymorphism, LAMP-1, as a predictor gene to inhibitors of microtubule dynamics using integrative analysis of pharmacogenetics and genomics." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-5458.
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He, Ping-Ping, Xin-Ping OuYang, Kai Yin, Wu-Jun Chen, Qian Lu, Zhong-Cheng Mo, Guo-Jun Zhao, Yun-Cheng Lv, and Chao-Ke Tang. "PDE Inhibitor Rolipram Increases Cholesterol Efflux and ABCA1 Expression: Rolipram Increases ABCA1 Expression." In 2012 International Conference on Biomedical Engineering and Biotechnology (iCBEB). IEEE, 2012. http://dx.doi.org/10.1109/icbeb.2012.292.
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Ji, Ning, Yuqi Yang, Chao-Yun Cai, Zi-Ning Lei, Jing-Quan Wang, Pranav Gupta, Suneet Shukla, Suresh V. Ambudkar, Dexin Kong, and Zhe-Sheng Chen. "Abstract 3796: Selonsertib, an ASK1 inhibitor, antagonizes ABCB1- and ABCG2-mediated chemotherapeutic drug resistance." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-3796.
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Ji, Ning, Yuqi Yang, Chao-Yun Cai, Zi-Ning Lei, Jing-Quan Wang, Pranav Gupta, Suneet Shukla, Suresh V. Ambudkar, Dexin Kong, and Zhe-Sheng Chen. "Abstract 3796: Selonsertib, an ASK1 inhibitor, antagonizes ABCB1- and ABCG2-mediated chemotherapeutic drug resistance." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-3796.
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Patel, Atish S., Amit Tiwari, Eduardo Chufan, Satyakam Singh, Kamlesh Sodani, Nagaraju Anreddy, Tanaji Talele, Suresh Ambudkar, Ralph Stephani, and Zhe-Sheng Chen. "Abstract 980: PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-980.
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