|
1
|
Liu J, Qu B, Wang S, Qian L, Liu F, Zhang X, Zhao Q, Chen Y, Chen W, Wang L, Zhang S. Fengshi gutong capsules attenuates CIA-induced RA bone destruction in rats by targeting TNF-α inhibition: Integration and experimental validation of network pharmacology and proteomics. JOURNAL OF ETHNOPHARMACOLOGY 2025; 344:119535. [PMID: 39987998 DOI: 10.1016/j.jep.2025.119535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 02/14/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Fengshi Gutong Capsule (FSGT) is a proprietary Chinese medicine with established clinical efficacy in Rheumatoid arthritis (RA); however, its underlying mechanisms remain unclear. AIM This study aims to elucidate the mechanisms by which FSGT alleviates RA. MATERIALS AND METHODS A collagen-induced arthritis (CIA) rat model was employed to assess the therapeutic effects of FSGT in RA. Network pharmacology and proteomics were integrated to identify potential mechanism and molecular targets, which were further validated via Western blot analysis. Molecular docking and microscale thermophoresis (MST) were utilized to assess the binding affinities of FSGT's active components to key proteins. RESULTS FSGT (280 and 840 mg/kg) alleviated CIA-induced RA in rats without significant side effects. Network pharmacology and label-free proteomic analysis displayed that FSGT exerted its therapeutic effects by modulating inflammation and bone destruction. FSGT significantly reduced serum levels of inflammatory cytokines and their protein expression in the ankle joints and synovial tissues. Additionally, FSGT attenuated bone destruction and significantly reversed the expression of bone destruction-related proteins. Molecular docking revealed that 18 active compounds in FSGT exhibited strong binding affinity for TNF-α, with hypaconitine, 18α-glycyrrhizic acid, and naringenin further validated by MST assays. CONCLUSION FSGT improved CIA-induced RA in rats by targeting TNF-α to reduce inflammation and inhibit bone destruction, offering insights into its therapeutic mechanisms in RA.
Collapse
Affiliation(s)
- Jiahui Liu
- Anhui University of Chinese Medicine, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, The Ministry of Education and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Biao Qu
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China
| | - Sheng Wang
- Center for Scientific Research, Anhui Medical University, Hefei, 230601, China
| | - Linkai Qian
- Anhui University of Chinese Medicine, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, The Ministry of Education and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Feifei Liu
- Anhui University of Chinese Medicine, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, The Ministry of Education and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Xueting Zhang
- Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Quan Zhao
- Bozhou China Sciences Testing Co. , Ltd., Bozhou, 236000, China
| | - Yunna Chen
- Anhui University of Chinese Medicine, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, The Ministry of Education and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Weidong Chen
- Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Lei Wang
- Anhui University of Chinese Medicine, Hefei, 230012, China.
| | - Sheng Zhang
- Anhui University of Chinese Medicine, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, The Ministry of Education and Key Laboratory of Molecular Biology (Brain Diseases), Anhui University of Chinese Medicine, Hefei, 230012, China; "The Classic and Innovation" Stroke Research Team, Anhui University of Chinese Medicine, Hefei, 230012, China.
| |
Collapse
|
|
2
|
Gao L, Meng F, Yang Z, Lafuente-Merchan M, Fernández LM, Cao Y, Kusamori K, Nishikawa M, Itakura S, Chen J, Huang X, Ouyang D, Riester O, Deigner HP, Lai H, Pedraz JL, Ramalingam M, Cai Y. Nano-drug delivery system for the treatment of multidrug-resistant breast cancer: Current status and future perspectives. Biomed Pharmacother 2024; 179:117327. [PMID: 39216449 DOI: 10.1016/j.biopha.2024.117327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/11/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024] Open
Abstract
Breast cancer (BC) is one of the most frequently diagnosed cancers in women. Chemotherapy continues to be the treatment of choice for clinically combating it. Nevertheless, the chemotherapy process is frequently hindered by multidrug resistance, thereby impacting the effectiveness of the treatment. Multidrug resistance (MDR) refers to the phenomenon in which malignant tumour cells develop resistance to anticancer drugs after one single exposure. It can occur with a broad range of chemotherapeutic drugs with distinct chemical structures and mechanisms of action, and it is one of the major causes of treatment failure and disease relapse. Research has long been focused on overcoming MDR by using multiple drug combinations, but this approach is often associated with serious side effects. Therefore, there is a pressing need for in-depth research into the mechanisms of MDR, as well as the development of new drugs to reverse MDR and improve the efficacy of breast cancer chemotherapy. This article reviews the mechanisms of multidrug resistance and explores the application of nano-drug delivery system (NDDS) to overcome MDR in breast cancer. The aim is to offer a valuable reference for further research endeavours.
Collapse
Affiliation(s)
- Lanwen Gao
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University / International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China / Guangdong Key Lab of Traditional Chinese Medicine Information Technology / International Science and Technology Cooperation Base of Guangdong Province / School of Pharmacy, Jinan University, Guangdong, Guangzhou 510632, China.
| | - Fansu Meng
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan 528400, China.
| | - Zhenjiang Yang
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China.
| | - Markel Lafuente-Merchan
- NanoBioCel Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz 01006, Spain; Bioaraba Health Research Institute, Jose Atxotegi, s/n, Vitoria-Gasteiz 01009, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, Madrid 28029, Spain.
| | - Laura Merino Fernández
- NanoBioCel Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz 01006, Spain; Bioaraba Health Research Institute, Jose Atxotegi, s/n, Vitoria-Gasteiz 01009, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, Madrid 28029, Spain.
| | - Ye Cao
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University / International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China / Guangdong Key Lab of Traditional Chinese Medicine Information Technology / International Science and Technology Cooperation Base of Guangdong Province / School of Pharmacy, Jinan University, Guangdong, Guangzhou 510632, China.
| | - Kosuke Kusamori
- Laboratory of Cellular Drug Discovery and Development, Faculty of Pharmaceutical Sciences Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
| | - Makiya Nishikawa
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
| | - Shoko Itakura
- Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
| | - Junqian Chen
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
| | - Xiaoxun Huang
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan 528400, China.
| | - Dongfang Ouyang
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, Boston, MA 02129, USA.
| | - Oliver Riester
- Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Villingen-Schwenningen 78054, Germany.
| | - Hans-Peter Deigner
- Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Villingen-Schwenningen 78054, Germany.
| | - Haibiao Lai
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan 528400, China.
| | - Jose Luis Pedraz
- NanoBioCel Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz 01006, Spain; Bioaraba Health Research Institute, Jose Atxotegi, s/n, Vitoria-Gasteiz 01009, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, Madrid 28029, Spain; Joint Research Laboratory (JRL) on Bioprinting and Advanced Pharma Development, A Joint Venture of TECNALIA (Basque Research and Technology Alliance), Centro de Investigación Lascaray Ikergunea, Avenida Miguel de Unamuno, Vitoria-Gasteiz 01006, Spain.
| | - Murugan Ramalingam
- NanoBioCel Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz 01006, Spain; Bioaraba Health Research Institute, Jose Atxotegi, s/n, Vitoria-Gasteiz 01009, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, Madrid 28029, Spain; Joint Research Laboratory (JRL) on Bioprinting and Advanced Pharma Development, A Joint Venture of TECNALIA (Basque Research and Technology Alliance), Centro de Investigación Lascaray Ikergunea, Avenida Miguel de Unamuno, Vitoria-Gasteiz 01006, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao 48013, Spain; School of Basic Medical Sciences, Binzhou Medical University, Yantai 264003, China.
| | - Yu Cai
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University / International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China / Guangdong Key Lab of Traditional Chinese Medicine Information Technology / International Science and Technology Cooperation Base of Guangdong Province / School of Pharmacy, Jinan University, Guangdong, Guangzhou 510632, China.
| |
Collapse
|
|
3
|
Kabir MZ, Tayyab H, Erkmen C, Mohamad SB, Uslu B. Comprehensive views toward the biomolecular recognition of an anticancer drug, leflunomide with human serum albumin. J Biomol Struct Dyn 2024; 42:7257-7271. [PMID: 37529911 DOI: 10.1080/07391102.2023.2239931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 07/16/2023] [Indexed: 08/03/2023]
Abstract
Biomolecular association of an anticancer drug, leflunomide (LEF) with human serum albumin (HSA), the leading ligands carrier in human circulation was characterized using biophysical (i.e., fluorescence, absorption and voltammetric) methods and computational (i.e., molecular docking and molecular dynamics simulation) techniques. Evaluations of fluorescence, absorption and voltammetric findings endorsed the complex formation between LEF and HSA. An inverse relationship of Stern-Volmer constant-temperature and hyperchromic shift of the protein's absorption signal with addition of LEF confirmed the LEF quenched the HSA fluorescence through static process. Moderate nature of binding strength (binding constant = 2.76-4.77 × 104 M-1) was detected towards the LEF-HSA complexation, while the association process was naturally driven via hydrophobic interactions, van der Waals interactions and hydrogen bonds, as evident from changes in entropy (ΔS= + 19.91 J mol-1 K-1) and enthalpy (ΔH = - 20.09 kJ mol-1), and molecular docking assessments. Spectral analyses of synchronous and three-dimensional fluorescence validated microenvironmental fluctuations near Trp and Tyr residues upon LEF binding to the protein. LEF association with HSA significantly defended temperature-induced destabilization of the protein. Although LEF was found to attach to HSA at Sudlow's sites I and II, but exhibited greater preference toward its site I, as detected by the investigations of competitive site-marker displacement. Molecular dynamics simulation assessment revealed that the complex attained equilibrium throughout simulations, showing the LEF-HSA complex constancy.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Md Zahirul Kabir
- Faculty of Pharmacy, Department of Analytical Chemistry, Ankara University, Ankara, Turkey
| | - Hafsa Tayyab
- Faculty of Science, Bioinformatics Programme, Institute of Biological Sciences, University of Malaya, Kuala Lumpur, Malaysia
| | - Cem Erkmen
- Faculty of Pharmacy, Department of Analytical Chemistry, Ankara University, Ankara, Turkey
| | - Saharuddin B Mohamad
- Faculty of Science, Bioinformatics Programme, Institute of Biological Sciences, University of Malaya, Kuala Lumpur, Malaysia
- Centre of Research for Computational Sciences and Informatics for Biology, Bioindustry, Environment, Agriculture and Healthcare, University of Malaya, Kuala Lumpur, Malaysia
| | - Bengi Uslu
- Faculty of Pharmacy, Department of Analytical Chemistry, Ankara University, Ankara, Turkey
| |
Collapse
|
|
4
|
Muller IB, Lin M, de Jonge R, Will N, López-Navarro B, van der Laken C, Struys EA, Oudejans CBM, Assaraf YG, Cloos J, Puig-Kröger A, Jansen G. Methotrexate Provokes Disparate Folate Metabolism Gene Expression and Alternative Splicing in Ex Vivo Monocytes and GM-CSF- and M-CSF-Polarized Macrophages. Int J Mol Sci 2023; 24:9641. [PMID: 37298590 PMCID: PMC10253671 DOI: 10.3390/ijms24119641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/26/2023] [Accepted: 05/28/2023] [Indexed: 06/12/2023] Open
Abstract
Macrophages constitute important immune cell targets of the antifolate methotrexate (MTX) in autoimmune diseases, including rheumatoid arthritis. Regulation of folate/MTX metabolism remains poorly understood upon pro-inflammatory (M1-type/GM-CSF-polarized) and anti-inflammatory (M2-type/M-CSF-polarized) macrophages. MTX activity strictly relies on the folylpolyglutamate synthetase (FPGS) dependent intracellular conversion and hence retention to MTX-polyglutamate (MTX-PG) forms. Here, we determined FPGS pre-mRNA splicing, FPGS enzyme activity and MTX-polyglutamylation in human monocyte-derived M1- and M2-macrophages exposed to 50 nmol/L MTX ex vivo. Moreover, RNA-sequencing analysis was used to investigate global splicing profiles and differential gene expression in monocytic and MTX-exposed macrophages. Monocytes displayed six-eight-fold higher ratios of alternatively-spliced/wild type FPGS transcripts than M1- and M2-macrophages. These ratios were inversely associated with a six-ten-fold increase in FPGS activity in M1- and M2-macrophages versus monocytes. Total MTX-PG accumulation was four-fold higher in M1- versus M2-macrophages. Differential splicing after MTX-exposure was particularly apparent in M2-macrophages for histone methylation/modification genes. MTX predominantly induced differential gene expression in M1-macrophages, involving folate metabolic pathway genes, signaling pathways, chemokines/cytokines and energy metabolism. Collectively, macrophage polarization-related differences in folate/MTX metabolism and downstream pathways at the level of pre-mRNA splicing and gene expression may account for variable accumulation of MTX-PGs, hence possibly impacting MTX treatment efficacy.
Collapse
Affiliation(s)
- Ittai B. Muller
- Department of Laboratory Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands; (I.B.M.); (M.L.); (R.d.J.); (E.A.S.); (C.B.M.O.)
| | - Marry Lin
- Department of Laboratory Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands; (I.B.M.); (M.L.); (R.d.J.); (E.A.S.); (C.B.M.O.)
| | - Robert de Jonge
- Department of Laboratory Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands; (I.B.M.); (M.L.); (R.d.J.); (E.A.S.); (C.B.M.O.)
| | - Nico Will
- Facility for Environment and Natural Science, Brandenburg Technical University Cottbus-Senftenberg, 01968 Senftenberg, Germany;
| | - Baltasar López-Navarro
- Laboratorio de Inmuno-Metabolismo e Inflamación, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital Gregorio Marañón, 28007 Madrid, Spain; (B.L.-N.); (A.P.-K.)
| | - Conny van der Laken
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center–location VUmc, 1081 HV Amsterdam, The Netherlands;
| | - Eduard A. Struys
- Department of Laboratory Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands; (I.B.M.); (M.L.); (R.d.J.); (E.A.S.); (C.B.M.O.)
| | - Cees B. M. Oudejans
- Department of Laboratory Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands; (I.B.M.); (M.L.); (R.d.J.); (E.A.S.); (C.B.M.O.)
| | - Yehuda G. Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel;
| | - Jacqueline Cloos
- Department of Hematology, Amsterdam University Medical Center–location VUmc, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands;
| | - Amaya Puig-Kröger
- Laboratorio de Inmuno-Metabolismo e Inflamación, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital Gregorio Marañón, 28007 Madrid, Spain; (B.L.-N.); (A.P.-K.)
| | - Gerrit Jansen
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center–location VUmc, 1081 HV Amsterdam, The Netherlands;
| |
Collapse
|
|
5
|
Hebing RC, Lin M, Bulatovic Calasan M, Muller IB, Mahmoud S, Heil S, Struys EA, van den Bemt BJ, Twisk JW, Lems W, Nurmohamed MT, Jansen G, de Jonge R. Pharmacokinetics of oral and subcutaneous methotrexate in red and white blood cells in patients with early rheumatoid arthritis: the methotrexate monitoring trial. Ann Rheum Dis 2023; 82:460-467. [PMID: 36543526 DOI: 10.1136/ard-2022-223398] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 11/21/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To investigate the pharmacokinetics of methotrexate polyglutamate (MTX-PG) accumulation in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) in patients with early rheumatoid arthritis (RA) after oral and subcutaneous MTX treatment. METHODS In a clinical prospective cohort study (Methotrexate Monitoring study), newly diagnosed patients with RA were randomised for oral or subcutaneous MTX. At 1, 2, 3 and 6 months after therapy initiation, blood was collected and RBCs and PBMCs were isolated. MTX-PG1-6 concentrations were determined by mass spectrometry methods using stable isotopes of MTX-PG1-6 as internal standards. RESULTS 43 patients (mean age: 58.5 years, 77% female) were included. PBMCs and RBCs revealed disparate pharmacokinetic profiles in both absolute MTX-PG accumulation levels and distribution profiles. Intracellular MTX-PG accumulation in PBMCs was significantly (p<0.001) 10-fold to 20-fold higher than RBCs at all time points, regardless of the administration route. MTX-PG distribution in PBMCs was composed of mostly MTX-PG1 (PG1>PG2>PG3). Remarkably, the distribution profile in PBMCs remained constant over 6 months. RBCs accumulated mainly MTX-PG1 and lower levels of MTX-PG2-5 at t=1 month. After 3 months, MTX-PG3 was the main PG-moiety in RBCs, a profile retained after 6 months of MTX therapy. Subcutaneous MTX administration results in higher RBC drug levels than after oral administration, especially shortly after treatment initiation. CONCLUSIONS This is the first study reporting disparate MTX-PG accumulation profiles in RBCs versus PBMCs in newly diagnosed patients with RA during 6 months oral or subcutaneous MTX administration. This analysis can contribute to improved MTX therapeutic drug monitoring for patients with RA. TRIAL REGISTRATION NUMBER NTR 7149.
Collapse
Affiliation(s)
- Renske Cf Hebing
- Reade, Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands
- Rheumatology, Amsterdam UMC VUMC Site, Amsterdam, The Netherlands
| | - Marry Lin
- Clinical Chemistry, Amsterdam UMC VUMC Site, Amsterdam, The Netherlands
| | - Maja Bulatovic Calasan
- Clinical Chemistry, Amsterdam UMC VUMC Site, Amsterdam, The Netherlands
- Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Ittai B Muller
- Clinical Chemistry, Amsterdam UMC VUMC Site, Amsterdam, The Netherlands
| | - Sohaila Mahmoud
- Reade, Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands
| | - Sandra Heil
- Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Eduard A Struys
- Clinical Chemistry, Amsterdam UMC VUMC Site, Amsterdam, The Netherlands
| | | | - Jos Wr Twisk
- Methodology and Applied Biostatistics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Willem Lems
- Reade, Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands
- Rheumatology, Amsterdam UMC VUMC Site, Amsterdam, The Netherlands
| | - Michael T Nurmohamed
- Reade, Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands
- Rheumatology, Amsterdam UMC VUMC Site, Amsterdam, The Netherlands
| | - Gerrit Jansen
- Rheumatology, Amsterdam UMC VUMC Site, Amsterdam, The Netherlands
| | - Robert de Jonge
- Clinical Chemistry, Amsterdam UMC VUMC Site, Amsterdam, The Netherlands
| |
Collapse
|
|
6
|
Wedam R, Greer YE, Wisniewski DJ, Weltz S, Kundu M, Voeller D, Lipkowitz S. Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer. Cancers (Basel) 2023; 15:cancers15071936. [PMID: 37046596 PMCID: PMC10093243 DOI: 10.3390/cancers15071936] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Breast cancer is the most frequently diagnosed malignancy worldwide and the leading cause of cancer mortality in women. Despite the recent development of new therapeutics including targeted therapies and immunotherapy, triple-negative breast cancer remains an aggressive form of breast cancer, and thus improved treatments are needed. In recent decades, it has become increasingly clear that breast cancers harbor metabolic plasticity that is controlled by mitochondria. A myriad of studies provide evidence that mitochondria are essential to breast cancer progression. Mitochondria in breast cancers are widely reprogrammed to enhance energy production and biosynthesis of macromolecules required for tumor growth. In this review, we will discuss the current understanding of mitochondrial roles in breast cancers and elucidate why mitochondria are a rational therapeutic target. We will then outline the status of the use of mitochondria-targeting drugs in breast cancers, and highlight ClpP agonists as emerging mitochondria-targeting drugs with a unique mechanism of action. We also illustrate possible drug combination strategies and challenges in the future breast cancer clinic.
Collapse
Affiliation(s)
- Rohan Wedam
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yoshimi Endo Greer
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - David J Wisniewski
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sarah Weltz
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Manjari Kundu
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Donna Voeller
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Stanley Lipkowitz
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| |
Collapse
|
|
7
|
Wang C, Tang H, Wang Y, Chang Y, Wu YJ, Wang B, Sun W, Xiao F, Wei W. CP-25 enhances OAT1-mediated absorption of methotrexate in synoviocytes of collagen-induced arthritis rats. Acta Pharmacol Sin 2023; 44:81-91. [PMID: 35732708 PMCID: PMC9813221 DOI: 10.1038/s41401-022-00931-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 05/26/2022] [Indexed: 01/18/2023]
Abstract
Organic anion transporter 1 (OAT1) plays a major role in mediating the absorption, distribution and excretion of drugs and other xenobiotics in the human body. In this study we explored the OAT1 status in rheumatoid arthritis (RA) patients and arthritic animals and its role in regulating the anti-arthritic activity of methotrexate (MTX). We showed that OAT1 expression was significantly downregulated in synovial tissues from RA patients compared with that in the control patients. In collagen-induced arthritis (CIA) rats, synovial OAT1 expression was significantly decreased compared with the control rats. In synoviocytes isolated from CIA rats, PGE2 (0.003-1.75 μM) dose-dependently downregulated OAT1 expression, resulting in decreased absorption of MTX. Silencing OAT1 in synoviocytes caused a 43.7% reduction in the uptake of MTX. Furthermore, knockdown of OAT1 impaired MTX-induced inhibitory effects on the viability and migration of synoviocytes isolated from CIA rats. Moreover, injection of OAT1-shRNA into articular cavity of CIA rats significantly decreased synovial OAT1 expression and impaired the anti-arthritic action of MTX, while injection of lentivirus containing OAT1 sequences led to the opposite results. Interestingly, we found that paeoniflorin-6'-O-benzene sulfonate (CP-25) upregulated OAT1 expression both in vitro and in vivo and promoted MTX uptake by synoviocytes via regulating OAT1 expression and function. Taken together, OAT1 plays a major role in regulating MTX uptake by synoviocytes and the anti-arthritic activity of MTX. OAT1 is downregulated in RA and CIA rats, which can be improved by CP-25.
Collapse
Affiliation(s)
- Chun Wang
- Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Hao Tang
- Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Yong Wang
- Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Yan Chang
- Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Yi-Jin Wu
- Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Bin Wang
- Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Wei Sun
- Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Feng Xiao
- Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China.
| |
Collapse
|
|
8
|
Gao J, Xiao N, Wang Q, Xu Z, Xiao F, Yang Z, Wei W, Wang C. OAT3 mediates methotrexate resistance in the treatment of rheumatoid arthritis. Biomed Pharmacother 2022; 153:113558. [DOI: 10.1016/j.biopha.2022.113558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/11/2022] [Accepted: 08/14/2022] [Indexed: 11/02/2022] Open
|
|
9
|
Research advances in the role and pharmaceuticals of ATP-binding cassette transporters in autoimmune diseases. Mol Cell Biochem 2022; 477:1075-1091. [PMID: 35034257 DOI: 10.1007/s11010-022-04354-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/06/2022] [Indexed: 10/19/2022]
Abstract
Autoimmune diseases are caused by the immune response of the body to its antigens, resulting in tissue damage. The pathogenesis of these diseases has not yet been elucidated. Most autoimmune diseases cannot be cured by effective drugs. The treatment strategy is to relieve the symptoms of the disease and balance the body's autoimmune function. The abnormal expression of ATP-binding cassette (ABC) transporters is directly related to the pathogenesis of autoimmune diseases and drug therapy resistance, which poses a great challenge for the drug therapy of autoimmune diseases. Therefore, this paper reviews the interplay between ABC transporters and the pathogenesis of autoimmune diseases to provide research progress and new ideas for the development of drugs in autoimmune diseases.
Collapse
|
|
10
|
Kukal S, Guin D, Rawat C, Bora S, Mishra MK, Sharma P, Paul PR, Kanojia N, Grewal GK, Kukreti S, Saso L, Kukreti R. Multidrug efflux transporter ABCG2: expression and regulation. Cell Mol Life Sci 2021; 78:6887-6939. [PMID: 34586444 PMCID: PMC11072723 DOI: 10.1007/s00018-021-03901-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/24/2021] [Accepted: 07/15/2021] [Indexed: 12/15/2022]
Abstract
The adenosine triphosphate (ATP)-binding cassette efflux transporter G2 (ABCG2) was originally discovered in a multidrug-resistant breast cancer cell line. Studies in the past have expanded the understanding of its role in physiology, disease pathology and drug resistance. With a widely distributed expression across different cell types, ABCG2 plays a central role in ATP-dependent efflux of a vast range of endogenous and exogenous molecules, thereby maintaining cellular homeostasis and providing tissue protection against xenobiotic insults. However, ABCG2 expression is subjected to alterations under various pathophysiological conditions such as inflammation, infection, tissue injury, disease pathology and in response to xenobiotics and endobiotics. These changes may interfere with the bioavailability of therapeutic substrate drugs conferring drug resistance and in certain cases worsen the pathophysiological state aggravating its severity. Considering the crucial role of ABCG2 in normal physiology, therapeutic interventions directly targeting the transporter function may produce serious side effects. Therefore, modulation of transporter regulation instead of inhibiting the transporter itself will allow subtle changes in ABCG2 activity. This requires a thorough comprehension of diverse factors and complex signaling pathways (Kinases, Wnt/β-catenin, Sonic hedgehog) operating at multiple regulatory levels dictating ABCG2 expression and activity. This review features a background on the physiological role of transporter, factors that modulate ABCG2 levels and highlights various signaling pathways, molecular mechanisms and genetic polymorphisms in ABCG2 regulation. This understanding will aid in identifying potential molecular targets for therapeutic interventions to overcome ABCG2-mediated multidrug resistance (MDR) and to manage ABCG2-related pathophysiology.
Collapse
Affiliation(s)
- Samiksha Kukal
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Debleena Guin
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Main Bawana Road, Delhi, 110042, India
| | - Chitra Rawat
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shivangi Bora
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Main Bawana Road, Delhi, 110042, India
| | - Manish Kumar Mishra
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Main Bawana Road, Delhi, 110042, India
| | - Priya Sharma
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
| | - Priyanka Rani Paul
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Neha Kanojia
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Gurpreet Kaur Grewal
- Department of Biotechnology, Kanya Maha Vidyalaya, Jalandhar, Punjab, 144004, India
| | - Shrikant Kukreti
- Nucleic Acids Research Lab, Department of Chemistry, University of Delhi (North Campus), Delhi, 110007, India
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, P. le Aldo Moro 5, 00185, Rome, Italy
| | - Ritushree Kukreti
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
| |
Collapse
|
|
11
|
Impact of ABCG2 Gene Polymorphism on the Predisposition to Psoriasis. Genes (Basel) 2021; 12:genes12101601. [PMID: 34680995 PMCID: PMC8535938 DOI: 10.3390/genes12101601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 09/27/2021] [Accepted: 10/08/2021] [Indexed: 11/29/2022] Open
Abstract
Psoriasis is a chronic inflammatory disease which is caused by the interaction between genetic and environmental factors. Evidence shows an association of psoriasis with co-morbidities including cardiovascular diseases, metabolic syndrome and hyperuricemia. Genome-wide association studies have revealed that the ABCG2 gene encoding ATP-binding cassette G2 protein was associated with inflammation and higher serum urate concentrations. In this study, we aimed to evaluate the role of ABCG2 gene polymorphisms on the susceptibility to psoriasis. The genotype distribution of two ABCG2 single nucleotide polymorphisms (SNPs), rs2231142 and rs2231137, was examined in 410 psoriasis patients and 1,089 gender-matched non-psoriasis controls. We found that heterozygotes (GT) for rs2231142 was associated with a decreased risk of psoriasis (p = 0.001; adjusted OR = 0.532; 95% CI, 0.370–0.765) after adjusting for age, as compared with homozygotes for the major allele (GG). Subjects who carried at least one polymorphic allele (homozygote or heterozygote for the minor allele) were less susceptible to psoriasis (p = 0.002; adjusted OR = 0.594; 95% CI, 0.249–0.823) and bearing higher serum urate levels (p = 0.026) than those homozygous for the major allele. Our results indicated that the ABCG2 gene polymorphism was associated with the risk of psoriasis.
Collapse
|
|
12
|
Muller IB, Lin M, Lems WF, Ter Wee MM, Wojtuszkiewicz A, Nurmohamed MT, Cloos J, Assaraf YG, Jansen G, de Jonge R. Association of altered folylpolyglutamate synthetase pre-mRNA splicing with methotrexate unresponsiveness in early rheumatoid arthritis. Rheumatology (Oxford) 2021; 60:1273-1281. [PMID: 32940699 PMCID: PMC7937028 DOI: 10.1093/rheumatology/keaa428] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 05/23/2020] [Indexed: 02/06/2023] Open
Abstract
Objectives An efficient pharmacological response to MTX treatment in RA patients relies on the retention and accumulation of intracellular MTX-polyglutamates catalysed by the enzyme folylpolyglutamate synthetase (FPGS). We recently identified a partial retention of FPGS intron 8 (8PR) as a prominent splice variant conferring FPGS dysfunction and decreased MTX polyglutamylation in acute lymphoblastic leukaemia. Here, we explored the association between FPGS 8PR levels and lack of MTX responsiveness in RA patients. Methods Thirty-six patients undergoing MTX treatment were enrolled from the Combinatie behandeling Reumatoide Artritis (COBRA)-light trial. RNA was isolated from blood samples at baseline, 13 weeks and 26 weeks of therapy, from patients in either COBRA-light (n = 21) or COBRA (n = 15) treatment arms. RT-qPCR analysis was used to assess RNA levels of FPGS 8PR over wild-type FPGS (8WT). Results In the COBRA-light treatment arm, higher baseline ratios of 8PR/8WT were significantly associated with higher 44-joint disease activity score (DAS44) at 13 and 26 weeks. Higher baseline ratios of 8PR/8WT also trended towards not obtaining low disease activity (DAS <1.6) and becoming a EULAR non-responder at 13 and 26 weeks. In the COBRA-treatment arm, a significant association was observed between high baseline 8PR/8WT ratios and higher DAS44 score at 26 weeks. Higher 8PR/8WT ratios were associated with non-response at week 26 based on both low disease activity and EULAR criteria. Conclusion This study is the first to associate alterations in FPGS pre-mRNA splicing levels with reduced responsiveness to MTX treatment in RA patients. Trial registration ISRCTN55552928.
Collapse
Affiliation(s)
- Ittai B Muller
- Department of Clinical Chemistry, Amsterdam, The Netherlands
| | - Marry Lin
- Department of Clinical Chemistry, Amsterdam, The Netherlands
| | - Willem F Lems
- Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands
| | - Marieke M Ter Wee
- Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands.,Department of Epidemiology and Biostatistics, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands
| | - Anna Wojtuszkiewicz
- Department of Hematology, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands
| | - Michael T Nurmohamed
- Amsterdam Rheumatology and Immunology Center, location Reade, Amsterdam, The Netherlands
| | - Jacqueline Cloos
- Department of Hematology, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | - Gerrit Jansen
- Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands
| | - Robert de Jonge
- Department of Clinical Chemistry, Amsterdam, The Netherlands
| |
Collapse
|
|
13
|
Jansen G, de Rotte MCFJ, de Jonge R. Smoking and Methotrexate Inefficacy in Rheumatoid Arthritis: What About Underlying Molecular Mechanisms? J Rheumatol 2021; 48:1495-1497. [PMID: 34329189 DOI: 10.3899/jrheum.210217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The study by Safy-Khan, et al in the current issue of The Journal of Rheumatology 1 reports that in a methotrexate (MTX)-based treatment regimen for patients with early arthritis, current smoking was significantly associated with a smaller reduction of Disease Activity Score in 28 joints (DAS28) over time compared to noncurrent smoking. This negative effect of current smoking on DAS28 was dose-dependent: patients who smoked 10-19 cigarettes per day did worse than patients who smoked 1-9 cigarettes per day.
Collapse
Affiliation(s)
- Gerrit Jansen
- G. Jansen, PhD, Biochemist, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, location VUmc; M.C. de Rotte, PhD, Clinical Chemist, R. de Jonge, PhD, Professor of Clinical Chemistry, Department of Clinical Chemistry, Amsterdam University Medical Center, Amsterdam, the Netherlands. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. G. Jansen, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, location VUmc, CCA - Rm 2.46, De Boelelaan 1117, 1081 HV Amsterdam, Amsterdam, the Netherlands,
| | - Maurits C F J de Rotte
- G. Jansen, PhD, Biochemist, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, location VUmc; M.C. de Rotte, PhD, Clinical Chemist, R. de Jonge, PhD, Professor of Clinical Chemistry, Department of Clinical Chemistry, Amsterdam University Medical Center, Amsterdam, the Netherlands. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. G. Jansen, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, location VUmc, CCA - Rm 2.46, De Boelelaan 1117, 1081 HV Amsterdam, Amsterdam, the Netherlands,
| | - Robert de Jonge
- G. Jansen, PhD, Biochemist, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, location VUmc; M.C. de Rotte, PhD, Clinical Chemist, R. de Jonge, PhD, Professor of Clinical Chemistry, Department of Clinical Chemistry, Amsterdam University Medical Center, Amsterdam, the Netherlands. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. G. Jansen, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, location VUmc, CCA - Rm 2.46, De Boelelaan 1117, 1081 HV Amsterdam, Amsterdam, the Netherlands,
| |
Collapse
|
|
14
|
Muto S, Minamitani N, Ogura T, Nakajima A, Nakagawa K, Masaka T, Hiura S, Kobayashi H, Kato H, Kameda H. Good response to methotrexate is associated with a decrease in the gene expression of ABCG2, a drug transporter, in patients with rheumatoid arthritis. Mod Rheumatol 2021; 31:1079-1086. [PMID: 33492182 DOI: 10.1080/14397595.2021.1879429] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVES Methotrexate (MTX) is used as an anchor drug in the treatment of rheumatoid arthritis (RA), although more than a half of the patients with RA require additional treatments. We designed a prospective study involving two medical centers in Japan to examine the association between the expression of MTX-related genes including a drug transporter ATP-binding cassette sub-family G member 2 (ABCG2) gene and the clinical response to MTX in MTX-naive patients with RA. METHODS The primary endpoint of this study was good response based on the European League Against Rheumatism (EULAR) response criteria by Disease Activity Score using 28-joint count (DAS28). We evaluated the association between the baseline expression of six genes involved in the intracellular pharmacokinetics of MTX, including ABCG2, as well as their temporal changes, and the clinical response at week 12 from the initiation of MTX. RESULTS Based on the clinical response at 12 weeks after the initiation of MTX, 24 patients were classified into good responders (n = 9) and non-good responders (n = 15; 10 moderate responders and 5 non-responders) groups. A univariate logistic regression analysis of the baseline gene expression levels to predict the EULAR good response at week 12 showed a significant association with ABCG2 expression alone. Furthermore, the rate of baseline expression of ABCG2 mRNA above the cut-off value determined using a receiver operating characteristic curve was higher in good responders than in non-good responders (p = .012). Moreover, ABCG2 expression decreased in almost all good responders, but not in non-good responders, after MTX treatment for 12 weeks (median -76% vs. +41% from baseline, respectively; p = .011). The ABCG2 expression level did not correlate with DAS28 at baseline or week 12. CONCLUSIONS Our study revealed that good response to MTX is associated with a decrease in the expression of ABCG2 in patients with RA.
Collapse
Affiliation(s)
- Satoshi Muto
- Center of Pharmaceutical Health Care and Sciences, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
| | - Nana Minamitani
- Center of Pharmaceutical Health Care and Sciences, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
| | - Takehisa Ogura
- Division of Rheumatology, Department of Internal Medicine, Toho University (Ohashi Medical Center), Tokyo, Japan
| | - Arata Nakajima
- Department of Orthopaedic Surgery, Toho University (Sakura Medical Center), Chiba, Japan
| | - Koichi Nakagawa
- Department of Orthopaedic Surgery, Toho University (Sakura Medical Center), Chiba, Japan
| | - Toru Masaka
- Center of Pharmaceutical Health Care and Sciences, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.,Department of Pharmacy, Toho University Sakura Medical Center, Chiba, Japan
| | - Sumiko Hiura
- Department of Pharmacy, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Hideki Kobayashi
- Department of Pharmacy, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Hiroyoshi Kato
- Center of Pharmaceutical Health Care and Sciences, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
| | - Hideto Kameda
- Division of Rheumatology, Department of Internal Medicine, Toho University (Ohashi Medical Center), Tokyo, Japan
| |
Collapse
|
|
15
|
Monitoring of Peripheral Blood Leukocytes and Plasma Samples: A Pilot Study to Examine Treatment Response to Leflunomide in Rheumatoid Arthritis. Pharmaceuticals (Basel) 2021; 14:ph14020106. [PMID: 33573015 PMCID: PMC7910893 DOI: 10.3390/ph14020106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/22/2021] [Accepted: 01/22/2021] [Indexed: 11/17/2022] Open
Abstract
Rheumatoid arthritis (RA) is a painful inflammatory disease of the joints which affects a considerable proportion of the world population, mostly women. If not adequately treated, RA patients can become permanently disabled. Importantly, not all the patients respond to the available anti-rheumatic therapies, which also present diverse side effects. In this context, monitoring of treatment response is pivotal to avoid unnecessary side effects and costs towards an ineffective therapy. Herein, we performed a pilot study to investigate the potential use of flow cytometry and attenuated total reflection–Fourier transform infrared (ATR-FTIR) spectroscopy as measures to identify responders and non-responders to leflunomide, a disease-modifying drug used in the treatment of RA patients. The evaluation of peripheral blood CD62L+ polymorphonuclear cell numbers and ATR-FTIR vibrational modes in plasma were able to discriminate responders to leflunomide (LFN) three-months after therapy has started. Overall, the results indicate that both flow cytometry and ATR-FTIR can potentially be employed as additional measures to monitor early treatment response to LFN in RA patients.
Collapse
|
|
16
|
Gao J, Wang C, Wei W. The effects of drug transporters on the efficacy of methotrexate in the treatment of rheumatoid arthritis. Life Sci 2021; 268:118907. [PMID: 33428880 DOI: 10.1016/j.lfs.2020.118907] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 12/08/2020] [Accepted: 12/10/2020] [Indexed: 12/12/2022]
Abstract
The ATP-binding cassette (ABC) and solute carrier (SLC) transporter families consist of common drug transporters that mediate the efflux and uptake of drugs, respectively, and play an important role in the absorption, distribution, metabolism and excretion of drugs in vivo. Rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis, and there are many RA patients worldwide. Methotrexate (MTX), the first-choice treatment for RA, can reduce the level of inflammation, prevent joint erosion and functional damage, and greatly reduce pain in RA patients. However, many patients show resistance to MTX, greatly affecting the efficacy of MTX. Many factors, such as irrational drug use and heredity, are associated with drug resistance. Considering the effect of drug transporters on drugs, many studies have compared the expression of drug transporters in drug-resistant and drug-sensitive patients, and abnormal transporter expression and transport activity have been found in patients with MTX resistance. Thus, drug transporters are involved in drug resistance. This article reviews the effects of transporters on the efficacy of MTX in the treatment of RA.
Collapse
Affiliation(s)
- Jinzhang Gao
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, China
| | - Chun Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, China.
| |
Collapse
|
|
17
|
Seelig A. P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers. Front Oncol 2020; 10:576559. [PMID: 33194688 PMCID: PMC7649427 DOI: 10.3389/fonc.2020.576559] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 08/31/2020] [Indexed: 12/31/2022] Open
Abstract
P-glycoprotein or multidrug resistance protein (MDR1) is an adenosine triphosphate (ATP) binding cassette transporter (ABCB1) intensely investigated because it is an obstacle to successful pharmacotherapy of cancers. P-glycoprotein prevents cellular uptake of a large number of structurally and functionally diverse compounds, including most cancer therapeutics and in this way causes multidrug resistance (MDR). To overcome MDR, and thus improve cancer treatment, an understanding of P-glycoprotein inhibition at the molecular level is required. With this goal in mind, we propose rules that predict whether a compound is a modulator, substrate, inhibitor, or inducer of P-glycoprotein. This new set of rules is derived from a quantitative analysis of the drug binding and transport properties of P-glycoprotein. We further discuss the role of P-glycoprotein in immune surveillance and cell metabolism. Finally, the predictive power of the proposed rules is demonstrated with a set of FDA approved drugs which have been repurposed for cancer therapy.
Collapse
Affiliation(s)
- Anna Seelig
- Biozentrum, University of Basel, Basel, Switzerland
| |
Collapse
|
|
18
|
The advances of methotrexate resistance in rheumatoid arthritis. Inflammopharmacology 2020; 28:1183-1193. [DOI: 10.1007/s10787-020-00741-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 07/23/2020] [Indexed: 12/14/2022]
|
|
19
|
Impairment of chemical hypoxia-induced sphingosine kinase-1 expression and activation in rheumatoid arthritis synovial fibroblasts: A signature of exhaustion? Biochem Pharmacol 2019; 165:249-262. [DOI: 10.1016/j.bcp.2019.02.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/08/2019] [Indexed: 12/28/2022]
|
|
20
|
Baghdadi LR, Woodman RJ, Shanahan EM, Wiese MD, Mangoni AA. Genetic polymorphism of the methotrexate transporter ABCG2, blood pressure and markers of arterial function in patients with rheumatoid arthritis: repeated cross-sectional study. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2018; 11:205-210. [PMID: 30519074 PMCID: PMC6237132 DOI: 10.2147/pgpm.s170557] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Purpose Methotrexate (MTX) treatment is associated with lower blood pressure (BP) and arterial stiffness in rheumatoid arthritis (RA). We investigated associations between single-nucleotide polymorphism (SNP) of the ATP-binding cassette efflux transporter gene ABCG2 (rs2231142), BP, and arterial stiffness in RA patients treated with MTX. Patients and methods Clinical and 24-hour peripheral and central BP, arterial wave reflection (Augmentation Index, AIx), arterial stiffness (Pulse Wave Velocity, PWV), and intracellular MTX polyglutamate (MTXPGs) concentrations were assessed in 56 RA patients on stable treatment with MTX using a repeated cross-sectional study design with measurements at baseline and after 8 months. Results Majority of the RA patients were homozygotes for the normal allele (CC, n=46) whereas 10 were rs2231142 heterozygotes (AC, n=10). MTXPGs concentrations were non-significantly higher in AC when compared to CC (144.3 vs 116.3 nmol/L packed RBCs, P=0.10). At baseline, the AC group had significantly lower age-adjusted clinical systolic BP (SBP) (P=0.01), 24-hour peripheral SBP (P=0.003), and central SBP (P=0.02) when compared to the CC group. However, AIx and PWV values were not significantly different between the two groups. When data from both visits were combined in a single analysis, and additionally adjusted for visit, gender, body mass index, and Disease Activity Score 28, the trend in SBP differences between-groups persisted but was no longer significant. Conclusion Future studies are required to test the hypothesis that this genetic polymorphism is associated with lower BP, arterial stiffness, and possibly, cardiovascular risk, in RA patients treated with MTX.
Collapse
Affiliation(s)
- Leena R Baghdadi
- Department of Family and Community Medicine, College of Medicine, King Saud University and King Khalid University Hospital, Riyadh, Saudi Arabia,
| | - Richard J Woodman
- Centre for Epidemiology and Biostatistics, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - E Michael Shanahan
- Department of Rheumatology, College of Medicine and Public Health, Flinders University and Southern Adelaide Local Health Network, Adelaide, SA, Australia
| | - Michael D Wiese
- School of Pharmacy and Medical Sciences and Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia
| | - Arduino A Mangoni
- Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University and Flinders Medical Centre, Adelaide, SA, Australia
| |
Collapse
|
|
21
|
Correlation Analysis of Potential Breast Cancer Resistance Protein Probes in Different Monolayer Systems. J Pharm Sci 2018; 107:2742-2747. [DOI: 10.1016/j.xphs.2018.07.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 06/22/2018] [Accepted: 07/17/2018] [Indexed: 01/23/2023]
|
|
22
|
Abderrazak A, El Azreq MA, Naci D, Fortin PR, Aoudjit F. Alpha2beta1 Integrin (VLA-2) Protects Activated Human Effector T Cells From Methotrexate-Induced Apoptosis. Front Immunol 2018; 9:2269. [PMID: 30374344 PMCID: PMC6197073 DOI: 10.3389/fimmu.2018.02269] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 09/12/2018] [Indexed: 01/18/2023] Open
Abstract
β1 integrins are critical for T cell migration, survival and costimulation. The integrin α2β1, which is a receptor for collagen, also named VLA-2, is a major costimulatory pathway of effector T cells and has been implicated in arthritis pathogenesis. Herein, we have examined its ability to promote methotrexate (MTX) resistance by enhancing effector T cells survival. Our results show that attachment of anti-CD3-activated human polarized Th17 cells to collagen but not to fibronectin or laminin led to a significant reduction of MTX-induced apoptosis. The anti-CD3+collagen-rescued cells still produce significant amounts of IL-17 and IFNγ upon their reactivation indicating that their inflammatory nature is preserved. Mechanistically, we found that the prosurvival role of anti-CD3+collagen involves activation of the MTX transporter ABCC1 (ATP Binding Cassette subfamily C Member 1). Finally, the protective effect of collagen/α2β1 integrin on MTX-induced apoptosis also occurs in memory CD4+ T cells isolated from rheumatoid arthritis (RA) patients suggesting its clinical relevance. Together these results show that α2β1 integrin promotes MTX resistance of effector T cells, and suggest that it could contribute to the development of MTX resistance that is seen in RA.
Collapse
Affiliation(s)
- Amna Abderrazak
- Axe de Recherche sur les Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU De Québec-Université Laval, Québec, QC, Canada
| | - Mohammed-Amine El Azreq
- Axe de Recherche sur les Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU De Québec-Université Laval, Québec, QC, Canada
| | - Dalila Naci
- Axe de Recherche sur les Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU De Québec-Université Laval, Québec, QC, Canada
| | - Paul R Fortin
- Axe de Recherche sur les Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU De Québec-Université Laval, Québec, QC, Canada.,Division de Rhumatologie, Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC, Canada
| | - Fawzi Aoudjit
- Axe de Recherche sur les Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU De Québec-Université Laval, Québec, QC, Canada.,Département de Microbiologie-Infectiologie et D'immunologie, Faculté de Médecine, Université Laval, Québec, QC, Canada
| |
Collapse
|
|
23
|
Wu YJ, Wang C, Wei W. The effects of DMARDs on the expression and function of P-gp, MRPs, BCRP in the treatment of autoimmune diseases. Biomed Pharmacother 2018; 105:870-878. [DOI: 10.1016/j.biopha.2018.06.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/24/2018] [Accepted: 06/04/2018] [Indexed: 12/17/2022] Open
|
|
24
|
Zhao E, Jiang X, Cui H. Bombyx mori Dihydroorotate Dehydrogenase: Knockdown Inhibits Cell Growth and Proliferation via Inducing Cell Cycle Arrest. Int J Mol Sci 2018; 19:ijms19092581. [PMID: 30200251 PMCID: PMC6163951 DOI: 10.3390/ijms19092581] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 08/22/2018] [Accepted: 08/26/2018] [Indexed: 12/03/2022] Open
Abstract
Dihydroorotate dehydrogenase (DHODH), in the de novo pyrimidine biosynthetic pathway, is the fourth enzyme of pyrimidine synthesis and is used to oxidize dihydroorotate and hence to orotat. We cloned and characterized here the dhod of silkworms, Bombyx mori. The full-length cDNA sequence of dhod is 1339 bp, including an open reading frame (ORF) of 1173 bp that encoded a 390 amino acid protein. And two domains were involved in the Dihydroorotate dehydrogenase amino acid sequence of silkworms, Bombyx mori (BmDHODH), namely a DHO_dh domain and a transmembrane domain in N-termina. The silkworm dhod is expressed throughout development and in nine tissues. Moreover, knockdown of the silkworm dhod gene reduced cell growth and proliferation through G2/M phase cell cycle arrest. Similarly, DHODH inhibitor (leflunomide) also reduced cell growth and proliferation, with a significant decrease of cyclin B and cdk2. DHODH is the fourth enzyme of pyrimidine synthesis, so we also found that leflunomide can inhibit, at least in part, the endomitotic DNA replication in silk glands cells. These findings demonstrate that downregulation of BmDHODH inhibits cell growth and proliferation in silkworm cells, and the endomitotic DNA replication in silk gland cells.
Collapse
Affiliation(s)
- Erhu Zhao
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400716, China.
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Chongqing 400716, China.
- Southwest University Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing 400715, China.
| | - Xiaolan Jiang
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400716, China.
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing 400716, China.
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Chongqing 400716, China.
- Southwest University Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing 400715, China.
| |
Collapse
|
|
25
|
Yu MB, Firek A, Langridge WHR. Predicting methotrexate resistance in rheumatoid arthritis patients. Inflammopharmacology 2018. [DOI: 10.1007/s10787-018-0459-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
|
|
26
|
Xiao W, Guo JP, Li C, Ye H, Wei W, Zou Y, Dai L, Li Z, Zhang M, Li X, Cai X, Zhao J, Wang Y, Tao Y, Liu D, Li Y, Wu M, Sun E, Wu L, Luo L, Mu R, Li Z. Genetic predictors of efficacy and toxicity of iguratimod in patients with rheumatoid arthritis. Pharmacogenomics 2018. [PMID: 29517409 DOI: 10.2217/pgs-2017-0162] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Iguratimod (IGU) is a novel disease-modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis (RA). Like other DMARDs, IGU exhibited significant differences in effectiveness and safety. AIM The aim of this study was to identify genetic predictorsof efficacyand toxicity of IGU in patients with RA. MATERIALS & METHODS Seven SNPs from IGU-metabolizing genes were genotyped in 272 IGU-treated patients with RA. Results: ABCG2 rs2231142 A allele conferred a higher response to IGU, while NAT2 rs1495742 G carriersconferred a lower response to IGU. CYP2C19*2 rs4244285 A carriers had higher risk for IGU-induced toxicity compared to the GG carriers. CONCLUSION Our study suggests that the polymorphisms of ABCG2 (rs2231142), NAT2 (rs1495741)and CYP2C19*2 (rs4244285) may help to predict thetherapeutic effectiveness and toxicity of IGU in patients with RA.
Collapse
Affiliation(s)
- Wenjing Xiao
- Department of Rheumatology & Immunology, People's Hospital, Peking University, Beijing, PR China
| | - Jian-Ping Guo
- Department of Rheumatology & Immunology, People's Hospital, Peking University, Beijing, PR China
| | - Chun Li
- Department of Rheumatology & Immunology, People's Hospital, Peking University, Beijing, PR China
| | - Hua Ye
- Department of Rheumatology & Immunology, People's Hospital, Peking University, Beijing, PR China
| | - Wei Wei
- Department of Rheumatology & Immunology, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Yaohong Zou
- Department of Rheumatology & Immunology, Wuxi People's Hospital, Wuxi, Jiangsu, PR China
| | - Lie Dai
- Department of Rheumatology & Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, PR China
| | - Zhijun Li
- Department of Rheumatology & Immunology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, PR China
| | - Miaojia Zhang
- Department of Rheumatology & Immunology, The First Affiliated Hospital with Nanjing, Nanjing, Jiangsu, PR China
| | - Xiangpei Li
- Department of Rheumatology & Immunology, Anhui Provincial Hospital, Hefei, Anhui, PR China
| | - Xiaoyan Cai
- Department of Rheumatology & Immunology, Guangzhou First People's Hospital, Guangzhou, Guangdong, PR China
| | - Jianhong Zhao
- Department of Rheumatology & Immunology, Jining No.1 People's Hospital, Jining, Shandong, PR China
| | - Youlian Wang
- Department of Rheumatology & Immunology, Jiangxi Provincial People's Hospital, Xinyu, Jiangxi, PR China
| | - Yi Tao
- Department of Rheumatology & Immunology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Dongzhou Liu
- Department of Rheumatology & Immunology, Shenzhen People's Hospital, Shenzhen, Guangzhou, PR China
| | - Yasong Li
- Department of Rheumatology & Immunology, Zhejiang Provincial People's Hospital, Huzhou, Zhejiang, PR China
| | - Min Wu
- Department of Rheumatology & Immunology, The First People's Hospital of Changzhou, Changzhou, Jiangsu, PR China
| | - Erwei Sun
- Department of Rheumatology & Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China
| | - Lijun Wu
- Department of Rheumatology & Immunology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uygur Autonomous Region, PR China
| | - Li Luo
- Department of Rheumatology & Immunology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, PR China
| | - Rong Mu
- Department of Rheumatology & Immunology, People's Hospital, Peking University, Beijing, PR China
| | - Zhanguo Li
- Department of Rheumatology & Immunology, People's Hospital, Peking University, Beijing, PR China
| |
Collapse
|
|
27
|
Dorasamy MS, Choudhary B, Nellore K, Subramanya H, Wong PF. Dihydroorotate dehydrogenase Inhibitors Target c-Myc and Arrest Melanoma, Myeloma and Lymphoma cells at S-phase. J Cancer 2017; 8:3086-3098. [PMID: 28928900 PMCID: PMC5604460 DOI: 10.7150/jca.14835] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 03/05/2017] [Indexed: 02/04/2023] Open
Abstract
Dihydroorotate dehydrogenase (DHODH) is a rate-limiting enzyme in the de novo biosynthesis pathway of pyrimidines. Inhibition of this enzyme impedes cancer cell proliferation but the exact mechanisms of action of these inhibitors in cancer cells are poorly understood. In this study, we showed that cancer cells, namely melanoma, myeloma and lymphoma overexpressed DHODH protein and treatment with A771726 and Brequinar sodium resulted in cell cycle arrest at S-phase. Transfection with DHODH shRNA depleted DHODH protein expression and impeded the proliferation of melanoma cells. shRNA knockdown of DHODH in combination with DHODH inhibitors further reduced the cancer cell proliferation, suggesting that knockdown of DHODH had sensitized the cells to DHODH inhibitors. Cell cycle regulatory proteins, c-Myc and its transcriptional target, p21 were found down- and up-regulated, respectively, following treatment with DHODH inhibitors in melanoma, myeloma and lymphoma cells. Interestingly, knockdown of DHODH by shRNA had also similarly affected the expression of c-Myc and p21 proteins. Our findings suggest that DHODH inhibitors induce cell cycle arrest in cancer cells via additional DHODH-independent pathway that is associated with p21 up-regulation and c-Myc down-regulation. Hence, DHODH inhibitors can be explored as potential therapeutic agents in cancer therapy.
Collapse
Affiliation(s)
- Mathura Subangari Dorasamy
- Department of Pharmacology, Faculty of Medicine, 50603 University of Malaya, Kuala Lumpur, Malaysia.,Aurigene Discovery Technologies Limited, Bollaram Road, Miyapur Hyderabad - 500049, Telangana, India
| | - Bhavesh Choudhary
- Aurigene Discovery Technologies Limited, Bollaram Road, Miyapur Hyderabad - 500049, Telangana, India
| | - Kavitha Nellore
- Aurigene Discovery Technologies Limited, 39-40, KIADB Industrial Area, Phase II Electronic City, Hosur Road, Bangalore - 560100 Karnataka, India
| | - Hosahalli Subramanya
- Aurigene Discovery Technologies Limited, 39-40, KIADB Industrial Area, Phase II Electronic City, Hosur Road, Bangalore - 560100 Karnataka, India
| | - Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, 50603 University of Malaya, Kuala Lumpur, Malaysia
| |
Collapse
|
|
28
|
Cleophas MC, Joosten LA, Stamp LK, Dalbeth N, Woodward OM, Merriman TR. ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2017; 10:129-142. [PMID: 28461764 PMCID: PMC5404803 DOI: 10.2147/pgpm.s105854] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
As a result of the association of a common polymorphism (rs2231142, Q141K) in the ATP-binding cassette G2 (ABCG2) transporter with serum urate concentration in a genome-wide association study, it was revealed that ABCG2 is an important uric acid transporter. This review discusses the relevance of ABCG2 polymorphisms in gout, possible etiological mechanisms, and treatment approaches. The 141K ABCG2 urate-increasing variant causes instability in the nucleotide-binding domain, leading to decreased surface expression and function. Trafficking of the protein to the cell membrane is altered, and instead, there is an increased ubiquitin-mediated proteasomal degradation of the variant protein as well as sequestration into aggresomes. In humans, this leads to decreased uric acid excretion through both the kidney and the gut with the potential for a subsequent compensatory increase in renal urinary excretion. Not only does the 141K polymorphism in ABCG2 lead to hyperuricemia through renal overload and renal underexcretion, but emerging evidence indicates that it also increases the risk of acute gout in the presence of hyperuricemia, early onset of gout, tophi formation, and a poor response to allopurinol. In addition, there is some evidence that ABCG2 dysfunction may promote renal dysfunction in chronic kidney disease patients, increase systemic inflammatory responses, and decrease cellular autophagic responses to stress. These results suggest multiple benefits in restoring ABCG2 function. It has been shown that decreased ABCG2 141K surface expression and function can be restored with colchicine and other small molecule correctors. However, caution should be exercised in any application of these approaches given the role of surface ABCG2 in drug resistance.
Collapse
Affiliation(s)
- M C Cleophas
- Department of Internal Medicine.,Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - L A Joosten
- Department of Internal Medicine.,Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - L K Stamp
- Department of Medicine, University of Otago Christchurch, Christchurch
| | - N Dalbeth
- Department of Medicine, University of Auckland, Auckland, New Zealand
| | - O M Woodward
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Tony R Merriman
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
| |
Collapse
|
|
29
|
Atisha-Fregoso Y, Lima G, Pascual-Ramos V, Baños-Peláez M, Fragoso-Loyo H, Jakez-Ocampo J, Contreras-Yáñez I, Llorente L. Rheumatoid Arthritis Disease Activity Is Determinant for ABCB1 and ABCG2 Drug-Efflux Transporters Function. PLoS One 2016; 11:e0159556. [PMID: 27442114 PMCID: PMC4956301 DOI: 10.1371/journal.pone.0159556] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 07/04/2016] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE To compare drug efflux function of ABCB1 and ABCG2 transporters in rheumatoid arthritis (RA) patients with active disease and in remission. METHODS Twenty two active RA patients (DAS28 ≥3.2) and 22 patients in remission (DAS28<2.6) were selected from an early RA clinic. All patients were evaluated at study inclusion and six months later. ABCB1 and ABCG2 functional activity was measured in peripheral lymphocytes by flow cytometry. The percentage of cells able to extrude substrates for ABCB1 and ABCG2 was recorded. RESULTS Active patients had higher ABCB1 and ABCG2 activity compared with patients in remission (median [interquartile range]): 3.9% (1.4-22.2) vs (1.3% (0.6-3.2), p = 0.003 and 3.9% (1.1-13.3) vs 0.9% (0.5-1.9) p = 0.006 respectively. Both transporters correlated with disease activity assessed by DAS28, rho = 0.45, p = 0.002 and rho = 0.47, p = 0.001 respectively. Correlation was observed between the time from the beginning of treatment and transporter activity: rho = 0.34, p = 0.025 for ABCB1 and rho = 0.35, p = 0.018 for ABCG2. The linear regression model showed that DAS28 and the time from the onset of treatment are predictors of ABCB1 and ABCG2 functional activity, even after adjustment for treatment. After six months we calculated the correlation between change in DAS28 and change in the functional activity in both transporters and found a moderate and significant correlation for ABCG2 (rho = 0.28, p = 0.04) and a non-significant correlation for ABCB1 (rho = 0.22, p = 0.11). CONCLUSIONS Patients with active RA have an increased function of ABCB1 and ABCG2, and disease activity is the main determinant of this phenomena.
Collapse
Affiliation(s)
- Yemil Atisha-Fregoso
- Division of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - Guadalupe Lima
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - Virginia Pascual-Ramos
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - Miguel Baños-Peláez
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - Hilda Fragoso-Loyo
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - Juan Jakez-Ocampo
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - Irazú Contreras-Yáñez
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - Luis Llorente
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| |
Collapse
|
|
30
|
Imamura H, Yoshina S, Ikari K, Miyazawa K, Momohara S, Mitani S. Impaired NFKBIE gene function decreases cellular uptake of methotrexate by down-regulating SLC19A1 expression in a human rheumatoid arthritis cell line. Mod Rheumatol 2016; 26:507-16. [PMID: 26587663 PMCID: PMC4898165 DOI: 10.3109/14397595.2015.1112481] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Objective: A non-synonymous single nucleotide polymorphism (nsSNP, rs2233434, Val194Ala) in the NFKBIE (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilon) gene is known to be a rheumatoid arthritis (RA) susceptibility polymorphism in the Japanese RA population and could be closely associated with nuclear factor kappaB (NF-κB) activity. Inflammation caused by RA is sometimes associated with changes in expression levels of MTX (methotrexate) pathway-related genes. It is of interest to examine whether the NFKBIE gene had any influences on the mode of MTX action. Methods: Both knockdown of NFKBIE gene expression and overexpression of wild-type NFKBIE and Val194Ala mutation were performed. A transfected human RA synovial cell line was cultured and then gene expressions in the MTX pathway were measured. In addition, we measured the uptake and efflux of MTX derivatives under the NFKBIE knockdown condition. Results: Knockdown of NFKBIE reduced the mRNA for SLC19A1, a main MTX membrane transporter, and the intracellular accumulations of MTX derivatives. Moreover, our experiments also confirmed that overexpression of Val194Ala mutant NFKBIE decreased the SLC19A1 mRNA when compared to that of wild-type NFKBIE. Conclusions: We suggest that the impairment of NFKBIE gene function can reduce the uptake of MTX into cells, suggesting that the gene is an important factor for the RA outcome.
Collapse
Affiliation(s)
- Hitoshi Imamura
- a Department of Physiology , Tokyo Women's Medical University School of Medicine , Tokyo , Japan .,b Institute of Rheumatology, Tokyo Women's Medical University , Tokyo , Japan
| | - Sawako Yoshina
- a Department of Physiology , Tokyo Women's Medical University School of Medicine , Tokyo , Japan
| | - Katsunori Ikari
- b Institute of Rheumatology, Tokyo Women's Medical University , Tokyo , Japan
| | - Keiji Miyazawa
- c Discovery Research III, Research and Development, Kissei Pharmaceutical Company , Nagano , Japan , and
| | - Shigeki Momohara
- b Institute of Rheumatology, Tokyo Women's Medical University , Tokyo , Japan
| | - Shohei Mitani
- a Department of Physiology , Tokyo Women's Medical University School of Medicine , Tokyo , Japan .,d Tokyo Women's Medical University Institute for Integrated Medical Sciences , Tokyo , Japan
| |
Collapse
|
|
31
|
Tsujimura S, Tanaka Y. Disease control by regulation of P-glycoprotein on lymphocytes in patients with rheumatoid arthritis. World J Exp Med 2015; 5:225-231. [PMID: 26618109 PMCID: PMC4655252 DOI: 10.5493/wjem.v5.i4.225] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Revised: 10/11/2014] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
The main purpose of treatment of rheumatoid arthritis (RA) with disease modifying antirheumatic drugs (DMARDs) is to control activation of lymphocytes, although some patients do not respond adequately to such treatment. Among various mechanisms of multidrug resistance, P-glycoprotein (P-gp), a member of ATP-binding cassette transporters, causes drug-resistance by efflux of intracellular drugs. Certain stimuli, such as tumor necrosis factor-α, activate lymphocytes and induce P-gp expression on lymphocytes, as evident in active RA. Studies from our laboratories showed spontaneous nuclear accumulation of human Y-box-binding protein-1, a multidrug resistance 1 transcription factor, in unstimulated lymphocytes, and surface overexpression of P-gp on peripheral lymphocytes of RA patients with high disease activity. The significant correlation between P-gp expression level and RA disease activity is associated with active efflux of drugs from the lymphocyte cytoplasm and in drug-resistance. However, the use of biological agents that reduce P-gp expression as well as P-gp antagonists (e.g., cyclosporine) can successfully reduce the efflux of corticosteroids from lymphocytes in vitro, suggesting that both types of drugs can be used to overcome drug-resistance and improve clinical outcome. We conclude that lymphocytes activated by various stimuli in RA patients with highly active disease acquire P-gp-mediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. Expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable therapeutic target to prevent drug resistance in patients with active RA.
Collapse
|
|
32
|
Romão VC, Lima A, Bernardes M, Canhão H, Fonseca JE. Three decades of low-dose methotrexate in rheumatoid arthritis: can we predict toxicity? Immunol Res 2015; 60:289-310. [PMID: 25391609 DOI: 10.1007/s12026-014-8564-6] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Methotrexate (MTX) is the anchor disease-modifying antirheumatic drug (DMARD) in rheumatoid arthritis (RA) treatment. It is used in monotherapy and/or in combination with other synthetic or biological DMARDs, and is known to have the best cost-effectiveness and efficacy/toxicity ratios. However, toxicity is still a concern, with a significant proportion of patients interrupting long-term treatment due to the occurrence of MTX-related adverse drug reactions (ADRs), which are the main cause of drug withdrawal. Despite the extensive accumulated experience in the last three decades, it is still impossible in routine clinical practice to identify patients prone to develop MTX toxicity. While clinical and biological variables, including folate supplementation, partially help to minimize MTX-related ADRs, the advent of pharmacogenomics could provide further insight into risk stratification and help to optimize drug monitoring and long-term retention. In this paper, we aimed to review and summarize current data on low-dose MTX-associated toxicity, its prevention and predictors, keeping in mind practical RA clinical care.
Collapse
Affiliation(s)
- Vasco C Romão
- Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon Academic Medical Centre, Edifício Egas Moniz, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal
| | | | | | | | | |
Collapse
|
|
33
|
Foti RS, Tyndale RF, Garcia KLP, Sweet DH, Nagar S, Sharan S, Rock DA. "Target-Site" Drug Metabolism and Transport. Drug Metab Dispos 2015; 43:1156-68. [PMID: 25986849 PMCID: PMC11024933 DOI: 10.1124/dmd.115.064576] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Accepted: 05/18/2015] [Indexed: 04/20/2024] Open
Abstract
The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014 Experimental Biology meeting in San Diego is summarized in this report. Emerging evidence has demonstrated that drug-metabolizing enzyme and transporter activity at the site of therapeutic action can affect the efficacy, safety, and metabolic properties of a given drug, with potential outcomes including altered dosing regimens, stricter exclusion criteria, or even the failure of a new chemical entity in clinical trials. Drug metabolism within the brain, for example, can contribute to metabolic activation of therapeutic drugs such as codeine as well as the elimination of potential neurotoxins in the brain. Similarly, the activity of oxidative and conjugative drug-metabolizing enzymes in the lung can have an effect on the efficacy of compounds such as resveratrol. In addition to metabolism, the active transport of compounds into or away from the site of action can also influence the outcome of a given therapeutic regimen or disease progression. For example, organic anion transporter 3 is involved in the initiation of pancreatic β-cell dysfunction and may have a role in how uremic toxins enter pancreatic β-cells and ultimately contribute to the pathogenesis of gestational diabetes. Finally, it is likely that a combination of target-specific metabolism and cellular internalization may have a significant role in determining the pharmacokinetics and efficacy of antibody-drug conjugates, a finding which has resulted in the development of a host of new analytical methods that are now used for characterizing the metabolism and disposition of antibody-drug conjugates. Taken together, the research summarized herein can provide for an increased understanding of potential barriers to drug efficacy and allow for a more rational approach for developing safe and effective therapeutics.
Collapse
Affiliation(s)
- Robert S Foti
- Amgen Pharmacokinetics and Drug Metabolism, Seattle, Washington (R.S.F., D.A.R.); Departments of Pharmacology and Toxicology and Psychiatry, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada (R.F.T., K.L.P.G.); Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (D.H.S.); School of Pharmacy, Temple University, Philadelphia, Pennsylvania (S.N.); and College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (S.S.)
| | - Rachel F Tyndale
- Amgen Pharmacokinetics and Drug Metabolism, Seattle, Washington (R.S.F., D.A.R.); Departments of Pharmacology and Toxicology and Psychiatry, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada (R.F.T., K.L.P.G.); Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (D.H.S.); School of Pharmacy, Temple University, Philadelphia, Pennsylvania (S.N.); and College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (S.S.)
| | - Kristine L P Garcia
- Amgen Pharmacokinetics and Drug Metabolism, Seattle, Washington (R.S.F., D.A.R.); Departments of Pharmacology and Toxicology and Psychiatry, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada (R.F.T., K.L.P.G.); Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (D.H.S.); School of Pharmacy, Temple University, Philadelphia, Pennsylvania (S.N.); and College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (S.S.)
| | - Douglas H Sweet
- Amgen Pharmacokinetics and Drug Metabolism, Seattle, Washington (R.S.F., D.A.R.); Departments of Pharmacology and Toxicology and Psychiatry, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada (R.F.T., K.L.P.G.); Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (D.H.S.); School of Pharmacy, Temple University, Philadelphia, Pennsylvania (S.N.); and College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (S.S.)
| | - Swati Nagar
- Amgen Pharmacokinetics and Drug Metabolism, Seattle, Washington (R.S.F., D.A.R.); Departments of Pharmacology and Toxicology and Psychiatry, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada (R.F.T., K.L.P.G.); Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (D.H.S.); School of Pharmacy, Temple University, Philadelphia, Pennsylvania (S.N.); and College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (S.S.)
| | - Satish Sharan
- Amgen Pharmacokinetics and Drug Metabolism, Seattle, Washington (R.S.F., D.A.R.); Departments of Pharmacology and Toxicology and Psychiatry, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada (R.F.T., K.L.P.G.); Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (D.H.S.); School of Pharmacy, Temple University, Philadelphia, Pennsylvania (S.N.); and College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (S.S.)
| | - Dan A Rock
- Amgen Pharmacokinetics and Drug Metabolism, Seattle, Washington (R.S.F., D.A.R.); Departments of Pharmacology and Toxicology and Psychiatry, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada (R.F.T., K.L.P.G.); Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (D.H.S.); School of Pharmacy, Temple University, Philadelphia, Pennsylvania (S.N.); and College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (S.S.)
| |
Collapse
|
|
34
|
Lima A, Sousa H, Monteiro J, Azevedo R, Medeiros R, Seabra V. Genetic polymorphisms in low-dose methotrexate transporters: current relevance as methotrexate therapeutic outcome biomarkers. Pharmacogenomics 2015; 15:1611-35. [PMID: 25340735 DOI: 10.2217/pgs.14.116] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Methotrexate (MTX) is used in low doses to treat a variety of diseases. Although the mechanism responsible for its therapeutic action is unknown, MTX membrane transport proteins (influx and/or efflux) can be major determinants of pharmacokinetics, adverse drug reactions and clinical response profiles. With progess in pharmacogenomics, the improvement of the prediction of patients' therapeutic outcome treated with low doses of MTX will offer a powerful tool for the translation of transporter SNPs into clinical practice and will be essential to sustain a breakthrough in the field of personalized medicine. Therefore, this paper provides an update on the current data on SNPs in genes encoding low-dose MTX membrane transport proteins and their relevance as possible biomarkers of MTX therapeutic outcome.
Collapse
Affiliation(s)
- Aurea Lima
- CESPU, Institute of Research & Advanced Training in Health Sciences & Technologies, Department of Pharmaceutical Sciences, Higher Institute of Health Sciences - North (ISCS-N), Rua Central de Gandra 1317, 4585-116, Gandra PRD, Portugal
| | | | | | | | | | | |
Collapse
|
|
35
|
Klukovits A, Krajcsi P. Mechanisms and therapeutic potential of inhibiting drug efflux transporters. Expert Opin Drug Metab Toxicol 2015; 11:907-20. [DOI: 10.1517/17425255.2015.1028917] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
|
|
36
|
García-Carrasco M, Mendoza-Pinto C, Macias Díaz S, Vera-Recabarren M, Vázquez de Lara L, Méndez Martínez S, Soto-Santillán P, González-Ramírez R, Ruiz-Arguelles A. P-glycoprotein in autoimmune rheumatic diseases. Autoimmun Rev 2015; 14:594-600. [PMID: 25712147 DOI: 10.1016/j.autrev.2015.02.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 02/16/2015] [Indexed: 11/29/2022]
Abstract
P-glycoprotein (Pgp) is a transmembrane protein of 170 kD encoded by the multidrug resistance 1 (MDR-1) gene, localized on chromosome 7. More than 50 polymorphisms of the MDR-1 gene have been described; a subset of these has been shown to play a pathophysiological role in the development of inflammatory bowel disease, femoral head osteonecrosis induced by steroids, lung cancer and renal epithelial tumors. Polymorphisms that have a protective effect on the development of conditions such as Parkinson disease have also been identified. P-glycoprotein belongs to the adenosine triphosphate binding cassette transporter superfamily and its structure comprises a chain of approximately 1280 aminoacid residues with an N-C terminal structure, arranged as 2 homologous halves, each of which has 6 transmembrane segments, with a total of 12 segments with 2 cytoplasmic nucleotide binding domains. Many cytokines like interleukin 2 and tumor necrosis factor alpha increase Pgp expression and activity. Pgp functions as an efflux pump for a variety of toxins in order to protect particular organs and tissues as the central nervous system. Pgp transports a variety of substrates including glucocorticoids while other drugs such as tacrolimus and cyclosporine A act as modulators of this protein. The most widely used method to measure Pgp activity is flow cytometry using naturally fluorescent substrates such as anthracyclines or rhodamine 123. The study of drug resistance and its association to Pgp began with the study of resistance to chemotherapy in the treatment of cancer and antiretroviral therapy for human immunodeficiency virus; however, the role of Pgp in the treatment of systemic lupus erythematosus, rheumatoid arthritis and psoriatic arthritis has been a focus of study lately and has emerged as an important mechanism by which treatment failure occurs. The present review analyzes the role of Pgp in these autoimmune diseases.
Collapse
Affiliation(s)
- M García-Carrasco
- Systemic Autoimmune Diseases Research Unit, Hospital General Regional No. 36, Instituto Mexicano del Seguro Social, Puebla, Mexico; Department of Immunology and Rheumatology, Medicine School, Benemérita Universidad Autónoma dePuebla, Puebla, Mexico.
| | - C Mendoza-Pinto
- Systemic Autoimmune Diseases Research Unit, Hospital General Regional No. 36, Instituto Mexicano del Seguro Social, Puebla, Mexico; Department of Immunology and Rheumatology, Medicine School, Benemérita Universidad Autónoma dePuebla, Puebla, Mexico.
| | - S Macias Díaz
- Systemic Autoimmune Diseases Research Unit, Hospital General Regional No. 36, Instituto Mexicano del Seguro Social, Puebla, Mexico.
| | | | - L Vázquez de Lara
- Departament of Experimental Medicine, Medicine School, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico.
| | - S Méndez Martínez
- Systemic Autoimmune Diseases Research Unit, Hospital General Regional No. 36, Instituto Mexicano del Seguro Social, Puebla, Mexico.
| | - P Soto-Santillán
- Systemic Autoimmune Diseases Research Unit, Hospital General Regional No. 36, Instituto Mexicano del Seguro Social, Puebla, Mexico.
| | - R González-Ramírez
- Systemic Autoimmune Diseases Research Unit, Hospital General Regional No. 36, Instituto Mexicano del Seguro Social, Puebla, Mexico.
| | - A Ruiz-Arguelles
- Laboratorios Clinicos de Puebla, Puebla, Mexico; Universidad de las Américas Puebla, Mexico.
| |
Collapse
|
|
37
|
Prasad S, Tripathi D, Rai MK, Aggarwal S, Mittal B, Agarwal V. Multidrug resistance protein-1 expression, function and polymorphisms in patients with rheumatoid arthritis not responding to methotrexate. Int J Rheum Dis 2014; 17:878-886. [PMID: 24734954 DOI: 10.1111/1756-185x.12362] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE To study the expression, function and polymorphism of MDR-1 protein on the peripheral blood lymphocytes in patients with RA following treatment with MTX and its relationship with response to therapy. METHODS RA patients naïve to MTX/DMARD- and glucocorticoid were enrolled. Expression and function of MDR-1 was carried out by flow cytometry at baseline and after 4 months of therapy. MDR-1 expression was measured by relative fluorescence intensities and percentage of positive cells. MDR-1 function was assessed by Rhodamine efflux in presence or absence of verapamil. Patients with reduction in disease activity score 28 ≥1.2 were defined as responders and <1.2 as non-responders. Three single nucleotide polymorphisms in MDR-1 gene, 3435T, 1236T and 2677T/A were studied. RESULTS Fifty-two patients of RA were grouped into responders (n = 41), and non-responders (n = 11) as per the defined criteria. There was no difference between the groups in terms of age, sex ratio or duration of illness, MTX dose and follow-up duration. The expression and function of the MDR-1 protein reduced significantly in the responder group after the treatment with MTX when compared to the baseline evaluation. The decrease was significant when compared to the non-responders at the fourth month. MDR-1 expression and function either increased or remained the same in the non-responder group after treatment with MTX. MTX unresponsiveness was not related to any of the three polymorphisms studied. CONCLUSION Persistent expression and function of MDR-1 identifies a subset of RA patients not responding to MTX. Its early recognition may help in appropriately modulating therapy.
Collapse
Affiliation(s)
- Shiva Prasad
- Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | | | | | | | | | | |
Collapse
|
|
38
|
Structure and function of BCRP, a broad specificity transporter of xenobiotics and endobiotics. Arch Toxicol 2014; 88:1205-48. [PMID: 24777822 DOI: 10.1007/s00204-014-1224-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 03/06/2014] [Indexed: 12/20/2022]
|
|
39
|
Blits M, Jansen G, Assaraf YG, van de Wiel MA, Lems WF, Nurmohamed MT, van Schaardenburg D, Voskuyl AE, Wolbink GJ, Vosslamber S, Verweij CL. Methotrexate Normalizes Up-Regulated Folate Pathway Genes in Rheumatoid Arthritis. ACTA ACUST UNITED AC 2013; 65:2791-802. [DOI: 10.1002/art.38094] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 07/11/2013] [Indexed: 12/19/2022]
Affiliation(s)
| | - Gerrit Jansen
- VU University Medical Center; Amsterdam The Netherlands
| | | | | | | | - Mike T. Nurmohamed
- VU University Medical Center, and Jan van Breemen Research Institute
- Reade; Amsterdam The Netherlands
| | - Dirkjan van Schaardenburg
- VU University Medical Center, and Jan van Breemen Research Institute
- Reade; Amsterdam The Netherlands
| | | | - Gert-Jan Wolbink
- Jan van Breemen Research Institute
- Reade; Amsterdam The Netherlands
| | | | | |
Collapse
|
|
40
|
van der Heijden JW, Assaraf YG, Gerards AH, Oerlemans R, Lems WF, Scheper RJ, Dijkmans BAC, Jansen G. Methotrexate analogues display enhanced inhibition of TNF-α production in whole blood from RA patients. Scand J Rheumatol 2013; 43:9-16. [PMID: 23987246 DOI: 10.3109/03009742.2013.797490] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVES Although methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA), patients experience clinical resistance to MTX upon prolonged treatment. We explored whether new-generation antifolates elicit superior anti-inflammatory properties when compared to MTX, based on their capacity to inhibit tumour necrosis factor (TNF)-α production. METHOD T cells in whole blood from 18 RA patients (including MTX-naïve, MTX- responsive, and MTX non-responsive patients) and seven healthy volunteers were stimulated with αCD3/αCD28 antibodies and incubated ex vivo for 72 h with MTX and eight novel antifolate drugs with potentially favourable biochemical and pharmacological properties. Drug concentrations exerting 50% inhibition (IC-50) of TNF-α production (by enzyme-linked immunosorbent assay, ELISA) were determined as an estimate for their anti-inflammatory capacity. In addition, induction of T-cell apoptosis was evaluated by flow cytometry. RESULTS The new-generation antifolates PT523, PT644, raltitrexed, and GW1843 proved to be potent inhibitors of TNF-α production in activated T cells from all three groups of RA patients and from healthy volunteers. Based on IC-50 values, these antifolates were up to 10.3 times more potent than MTX. The anti-inflammatory effects were observed at drug concentrations that provoked suppression of T-cell activation and induction of apoptosis in 20-40% of activated T cells. CONCLUSION In an ex-vivo setting, novel antifolates elicited marked inhibition of TNF-α production in activated T cells from RA patients. Further clinical evaluation is warranted to investigate whether a low dosage of these antifolates can elicit immunosuppressive effects equivalent to MTX, and whether they are superior to MTX in patients who fail to respond to MTX.
Collapse
Affiliation(s)
- J W van der Heijden
- Department of Rheumatology, VU University Medical Center , Amsterdam , The Netherlands
| | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Zhu S, Yan X, Xiang Z, Ding HF, Cui H. Leflunomide reduces proliferation and induces apoptosis in neuroblastoma cells in vitro and in vivo. PLoS One 2013; 8:e71555. [PMID: 23977077 PMCID: PMC3743402 DOI: 10.1371/journal.pone.0071555] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 07/01/2013] [Indexed: 11/30/2022] Open
Abstract
Leflunomide as an immunosuppressive drug is generally used in the treatment of rheumatoid arthritis. It inhibits DHODH (dihydroorotate dehydrogenase ), which is one of the essential enzymes in the de novo pyrimidine biosynthetic pathway. Here we showed that leflunomide significantly reduced cell proliferation and self-renewal activity. Annexin V-FITC/PI staining assay revealed that leflunomide induced S-phase cell cycle arrest, and promoted cell apoptosis. In vivo xenograft study in SCID mice showed that leflunomide inhibited tumor growth and development. We also observed that DHODH was commonly expressed in neuroblastoma. When treated with leflunomide, the neuroblastoma cell lines BE(2)-C, SK-N-DZ, and SK-N-F1 showed dramatic inhibition of DHODH at mRNA and protein levels. Considering the favorable toxicity profile and the successful clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in neuroblastoma.
Collapse
Affiliation(s)
- Shunqin Zhu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
- College of Life Science, Southwest University, Chongqing, China
| | - Xiaomin Yan
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Zhonghuai Xiang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Han-Fei Ding
- Cancer Center and Department of Pathology, Georgia Health Sciences University, Augusta, Georgia, United States of America
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
- * E-mail:
| |
Collapse
|
|
42
|
Stamp LK, Hazlett J, Highton J, Hessian PA. Expression of Methotrexate Transporters and Metabolizing Enzymes in Rheumatoid Synovial Tissue. J Rheumatol 2013; 40:1519-22. [DOI: 10.3899/jrheum.130066] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Objective.To determine whether methotrexate (MTX) affects the expression of genes involved in the transport [SLC19A1 (RFC1), ABCB1 (MDR1), ABCC1 (multidrug resistance proteins 1), ABCG2 (BCRP)], metabolism [γ-glutamyl hydrolase (GGH), folylpolyglutamate synthetase (FPGS)], and mechanism of action of MTX [thymidylate synthase, MTR, MTRR] in rheumatoid synovium.Methods.Synovial tissue samples were obtained from 20 patients with rheumatoid arthritis (RA). Gene expression was undertaken using quantitative real-time PCR.Results.All the genes examined were expressed in all samples. Expression of SLC19A1, GGH, FPGS, ABCC1, and MTRR was significantly higher in patients receiving MTX compared to those not receiving MTX (p < 0.05). The ratio of FPGS:GGH gene expression was 2.7 ± 0.51 ng/ml GAPDH (range 0.67–9.58).Conclusion.Genes involved in the transport, metabolism, and mechanism of action of MTX are expressed in rheumatoid joint synovium. These data provide evidence that MTX has the potential to be polyglutamated within the joint. The higher expression of FPGS compared to GGH in synovial tissue might favor production of long-chain MTX polyglutamates. Thus MTX has the potential to exert its therapeutic effects at the primary site of the inflammatory process in RA.
Collapse
|
|
43
|
Foster JG, Blunt MD, Carter E, Ward SG. Inhibition of PI3K signaling spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies. Pharmacol Rev 2012; 64:1027-54. [PMID: 23023033 DOI: 10.1124/pr.110.004051] [Citation(s) in RCA: 96] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The phosphoinositide 3-kinase/mammalian target of rapamycin/protein kinase B (PI3K/mTOR/Akt) signaling pathway is central to a plethora of cellular mechanisms in a wide variety of cells including leukocytes. Perturbation of this signaling cascade is implicated in inflammatory and autoimmune disorders as well as hematological malignancies. Proteins within the PI3K/mTOR/Akt pathway therefore represent attractive targets for therapeutic intervention. There has been a remarkable evolution of PI3K inhibitors in the past 20 years from the early chemical tool compounds to drugs that are showing promise as anticancer agents in clinical trials. The use of animal models and pharmacological tools has expanded our knowledge about the contribution of individual class I PI3K isoforms to immune cell function. In addition, class II and III PI3K isoforms are emerging as nonredundant regulators of immune cell signaling revealing potentially novel targets for disease treatment. Further complexity is added to the PI3K/mTOR/Akt pathway by a number of novel signaling inputs and feedback mechanisms. These can present either caveats or opportunities for novel drug targets. Here, we consider recent advances in 1) our understanding of the contribution of individual PI3K isoforms to immune cell function and their relevance to inflammatory/autoimmune diseases as well as lymphoma and 2) development of small molecules with which to inhibit the PI3K pathway. We also consider whether manipulating other proximal elements of the PI3K signaling cascade (such as class II and III PI3Ks or lipid phosphatases) are likely to be successful in fighting off different immune diseases.
Collapse
Affiliation(s)
- John G Foster
- Inflammatory Cell Biology Laboratory, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, UK.
| | | | | | | |
Collapse
|
|
44
|
Hashizume M, Yoshida H, Tanaka K, Suzuki M, Matsumoto I, Sumida T, Mihara M. Interleukin-6 regulates anti-arthritic effect of methotrexate via reduction of SLC19A1 expression in a mouse arthritis model. Arthritis Res Ther 2012; 14:R96. [PMID: 22546471 PMCID: PMC3446470 DOI: 10.1186/ar3821] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2011] [Revised: 04/09/2012] [Accepted: 04/30/2012] [Indexed: 05/14/2023] Open
Abstract
Introduction Methotrexate (MTX) enters cells via the reduced folate carrier SLC19A1, suggesting that SLC19A1 is associated with the efficacy of MTX. We here examined the relationship between the efficacy of MTX and the expression of SLC19A1 in glucose 6-phosphate isomerase (GPI)-induced arthritis. We found that interleukin-6 (IL-6) regulated the expression of SLC19A1, so we studied the effect of a combination of MTX and anti-mouse IL-6 receptor antibody (MR16-1). Methods GPI-induced arthritis was induced by intradermal immunization with recombinant GPI. MTX was given from the first day of immunization. Mice were injected once with MR16-1 10 days after immunization. The levels of SLC19A1 mRNA in whole hind limbs and immune cells were measured. Synovial cells from arthritic mice were cultured with cytokines, and cell proliferation and gene expressions were measured. Results MTX inhibited the development of GPI-induced arthritis; however, the efficacy of MTX gradually diminished. SLC19A1 expression in immunized mice with arthritis was lower than in intact mice; moreover, SLC19A1 expression in arthritic mice was further decreased when they were treated with MTX. IL-6 was highly expressed in whole hind limbs of arthritic mice. In an in vitro study using synovial cells from arthritic mice, IL-6 + soluble IL-6 receptor (sIL-6R) weakened the anti-proliferative effect of MTX and reduced SLC19A1 expression. Finally, although MR16-1 did not improve arthritis at all when administered on day 10, MTX in combination with MR16-1 more potently reduced the development of arthritis than did MTX alone. When used in combination with MTX, MR16-1 apparently reversed the decrease in SLC19A1 induced by MTX alone. Conclusions In the present study, we demonstrated for the first time that IL-6 reduced the efficacy of MTX by decreasing the expression of SLC19A1, which is important for MTX uptake into cells.
Collapse
Affiliation(s)
- Misato Hashizume
- Product Research Department, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co,, Ltd,, 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
45
|
Vieira-Sousa E, Gerlag DM, Tak PP. Synovial tissue response to treatment in rheumatoid arthritis. Open Rheumatol J 2011; 5:115-22. [PMID: 22279510 PMCID: PMC3263447 DOI: 10.2174/1874312901105010115] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2011] [Revised: 10/05/2011] [Accepted: 10/10/2011] [Indexed: 12/31/2022] Open
Abstract
The recognition of the synovial tissue, as the primary target of inflammation in RA, has driven research in this field, not only to clarify the disease pathogenesis but also to evaluate local changes in response to treatment. Special interest has been given to the identification of sensitive synovial biomarkers that could be of help in demonstrating proof of principle in early stages of drug development. Synovial sublining macrophages have been shown to correlate with scores for disease activity in cross-sectional studies. Moreover, decreased disease activity as measured by the disease activity score evaluated in 28 joints (DAS28) after effective treatment, has consistently been associated with a reduction of the number of CD68+ synovial sublining macrophages across different therapies. This observation highlights a possible final common pathway in the mechanism of action of various therapies and supports the notion that macrophages have a central role in RA pathogenesis. When considering experimental therapies, the study of serial synovial biopsies in relatively small numbers of patients, in the context of proof of principle trials, successfully distinguished between effective and ineffective treatments. This attractive approach can be used during early drug development for screening proposes, supporting which new treatments have higher probability to be beneficial in a large scale clinical trial. In this paper we review the effects of RA treatments on the synovial tissue, including targeted therapies, with particular attention to their effect on synovial biomarkers.
Collapse
Affiliation(s)
- Elsa Vieira-Sousa
- Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal
| | | | | |
Collapse
|
|
46
|
Chernajovsky Y. The importance of understanding the molecular mechanisms of resistance to biologics. Rheumatology (Oxford) 2011; 51:397-8. [PMID: 21984767 DOI: 10.1093/rheumatology/ker313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
|
|
47
|
Tsujimura S, Tanaka Y. Treatment strategy based on targeting P-glycoprotein on peripheral lymphocytes in patients with systemic autoimmune disease. Clin Exp Nephrol 2011; 16:102-8. [PMID: 21847519 DOI: 10.1007/s10157-011-0520-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2011] [Accepted: 07/29/2011] [Indexed: 12/22/2022]
Abstract
Although corticosteroids, immunosuppressants and disease-modifying antirheumatic drugs (DMARDs) are widely used in the treatment of various systemic autoimmune diseases such as systemic lupus erythematosus (SLE), we often experience patients with systemic autoimmune diseases who are resistant to these treatments. P-glycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, is known to play a pivotal role in the acquisition of drug resistance to chemotherapy in malignancy. However, the relevance of MDR-1 and P-gp to resting and activated lymphocytes, which are the major target in the treatment of systemic autoimmune diseases, remains unclear. Studies from our laboratories found surface expression of P-gp on peripheral lymphocytes in patients with SLE and a significant correlation between the expression level and disease activity. Such expression is induced not only by genotoxic stresses but also by various stimuli including cytokines, resulting in active efflux of drugs from the cytoplasm of lymphocytes, resulting in drug-resistance and high disease activity. However, the use of both P-gp antagonists (e.g., cyclosporine) and inhibition of P-gp synthesis with intensive immunosuppressive therapy successfully reduces the efflux of corticosteroids from lymphocytes in vitro, suggesting that P-gp antagonists and P-gp synthesis inhibitors could be used to overcome drug-resistance in vivo and improve outcome. In conclusion, lymphocytes activated by various stimuli in patients with highly active disease apparently acquire MDR-1-mediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. The expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable target to combat drug resistance in patients with active systemic autoimmune diseases.
Collapse
MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors
- ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Antirheumatic Agents/therapeutic use
- Autoimmune Diseases/blood
- Autoimmune Diseases/drug therapy
- Humans
- Immunosuppressive Agents/therapeutic use
- Lupus Erythematosus, Systemic/drug therapy
- Lupus Erythematosus, Systemic/immunology
- Lymphocytes/metabolism
Collapse
Affiliation(s)
- Shizuyo Tsujimura
- The First Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu, 807-8555, Japan
| | | |
Collapse
|
|
48
|
Lebedeva IV, Pande P, Patton WF. Sensitive and specific fluorescent probes for functional analysis of the three major types of mammalian ABC transporters. PLoS One 2011; 6:e22429. [PMID: 21799851 PMCID: PMC3142157 DOI: 10.1371/journal.pone.0022429] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Accepted: 06/23/2011] [Indexed: 11/18/2022] Open
Abstract
An underlying mechanism for multi drug resistance (MDR) is up-regulation of the transmembrane ATP-binding cassette (ABC) transporter proteins. ABC transporters also determine the general fate and effect of pharmaceutical agents in the body. The three major types of ABC transporters are MDR1 (P-gp, P-glycoprotein, ABCB1), MRP1/2 (ABCC1/2) and BCRP/MXR (ABCG2) proteins. Flow cytometry (FCM) allows determination of the functional expression levels of ABC transporters in live cells, but most dyes used as indicators (rhodamine 123, DiOC2(3), calcein-AM) have limited applicability as they do not detect all three major types of ABC transporters. Dyes with broad coverage (such as doxorubicin, daunorubicin and mitoxantrone) lack sensitivity due to overall dimness and thus may yield a significant percentage of false negative results. We describe two novel fluorescent probes that are substrates for all three common types of ABC transporters and can serve as indicators of MDR in flow cytometry assays using live cells. The probes exhibit fast internalization, favorable uptake/efflux kinetics and high sensitivity of MDR detection, as established by multidrug resistance activity factor (MAF) values and Kolmogorov-Smirnov statistical analysis. Used in combination with general or specific inhibitors of ABC transporters, both dyes readily identify functional efflux and are capable of detecting small levels of efflux as well as defining the type of multidrug resistance. The assay can be applied to the screening of putative modulators of ABC transporters, facilitating rapid, reproducible, specific and relatively simple functional detection of ABC transporter activity, and ready implementation on widely available instruments.
Collapse
Affiliation(s)
- Irina V Lebedeva
- ENZO Life Sciences, Inc., Farmingdale, New York, United States of America.
| | | | | |
Collapse
|
|
49
|
Elsby R, Fox L, Stresser D, Layton M, Butters C, Sharma P, Smith V, Surry D. In vitro risk assessment of AZD9056 perpetrating a transporter-mediated drug–drug interaction with methotrexate. Eur J Pharm Sci 2011; 43:41-9. [DOI: 10.1016/j.ejps.2011.03.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2010] [Revised: 01/14/2011] [Accepted: 03/17/2011] [Indexed: 11/30/2022]
|
|
50
|
Kooij G, Mizee MR, van Horssen J, Reijerkerk A, Witte ME, Drexhage JAR, van der Pol SMA, van Het Hof B, Scheffer G, Scheper R, Dijkstra CD, van der Valk P, de Vries HE. Adenosine triphosphate-binding cassette transporters mediate chemokine (C-C motif) ligand 2 secretion from reactive astrocytes: relevance to multiple sclerosis pathogenesis. ACTA ACUST UNITED AC 2010; 134:555-70. [PMID: 21183485 DOI: 10.1093/brain/awq330] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Adenosine triphosphate-binding cassette efflux transporters are highly expressed at the blood-brain barrier and actively hinder passage of harmful compounds, thereby maintaining brain homoeostasis. Since, adenosine triphosphate-binding cassette transporters drive cellular exclusion of potential neurotoxic compounds or inflammatory molecules, alterations in their expression and function at the blood-brain barrier may contribute to the pathogenesis of neuroinflammatory disorders, such as multiple sclerosis. Therefore, we investigated the expression pattern of different adenosine triphosphate-binding cassette efflux transporters, including P-glycoprotein, multidrug resistance-associated proteins-1 and -2 and breast cancer resistance protein in various well-characterized human multiple sclerosis lesions. Cerebrovascular expression of P-glycoprotein was decreased in both active and chronic inactive multiple sclerosis lesions. Interestingly, foamy macrophages in active multiple sclerosis lesions showed enhanced expression of multidrug resistance-associated protein-1 and breast cancer resistance protein, which coincided with their increased function of cultured foamy macrophages. Strikingly, reactive astrocytes display an increased expression of P-glycoprotein and multidrug resistance-associated protein-1 in both active and inactive multiple sclerosis lesions, which correlated with their enhanced in vitro activity on astrocytes derived from multiple sclerosis lesions. To investigate whether adenosine triphosphate-binding cassette transporters on reactive astrocytes can contribute to the inflammatory process, primary cultures of reactive human astrocytes were generated through activation of Toll-like receptor-3 to mimic the astrocytic phenotype as observed in multiple sclerosis lesions. Notably, blocking adenosine triphosphate-binding cassette transporter activity on reactive astrocytes inhibited immune cell migration across a blood-brain barrier model in vitro, which was due to the reduction of astrocytic release of the chemokine (C-C motif) ligand 2. Our data point towards a novel (patho)physiological role for adenosine triphosphate-binding cassette transporters, suggesting that limiting their activity by dampening astrocyte activation may open therapeutic avenues to diminish tissue damage during multiple sclerosis pathogenesis.
Collapse
Affiliation(s)
- Gijs Kooij
- Blood-Brain Barrier Research Group, Department of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, The Netherlands
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|