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Schmiech M, Abdel-Kahaar E, Ulrich J, Pfeiffer M, Duweb A, Zolk O, Syrovets T, Simmet T. Single-dose comparative pharmacokinetic/pharmacodynamic study of a micellar formulation versus a native Boswellia serrata dry extract in healthy volunteers. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155863. [PMID: 39033725 DOI: 10.1016/j.phymed.2024.155863] [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: 04/08/2024] [Revised: 06/18/2024] [Accepted: 07/08/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND Extracts of oleogum resins of Boswellia trees possess anti-inflammatory activities. Micellar formulations have been developed to increase the oral bioavailability of bioactive boswellic and lupeolic acids. PURPOSE The current single-dose crossover clinical trial compares for the first time pharmacokinetics/pharmacodynamics of two Boswellia serrata nutraceuticals, native Biotikon® BS-85 and micellar Boswellia-Loges®. METHODS After oral administration of the study preparations (800 mg) to 20 healthy volunteers, plasma concentrations of 8 boswellic and lupeolic acids were measured by using HPLC-MS/MS for up to 48 h Blood samples collected 2 and 5 h after drug administration were stimulated for 24 h with endotoxic lipopolysaccharide. The release of proinflammatory cytokines analyzed by flow cytometry was used as readout of the pharmacodynamic properties of the preparations. REGISTRATION German Clinical Trials Register (DRKS) No. DRKS00027369. RESULTS Administration of the micellar extract significantly increased Cmax, AUC0-48, and shortened Tmax for all boswellic and lupeolic acids compared to native extract. Accordingly, their relative bioavailability increased to 1,720-4,291 % with the highest difference for acetyl-11-keto-β-boswellic acid (AKBA). Both preparations reduced the release of TNF-α and the native formulation diminished also IL-1β and IL-6. However, no significant differences were observed between the preparations, except for a higher decrease in IL-1β by the native formulation Biotikon® BS-85. In a lymphocytic gene reporter cell line, both nutraceuticals similarly inhibited the NF-κB transcription factor activity as well as the TNF-α release, yet the native formulation Biotikon®BS-85 was more efficient in inhibiting TNF-α. CONCLUSION Administration of the micellar Boswellia serrata nutraceutical increased the oral bioavailability of boswellic and lupeolic acids. Yet, the increase in plasma concentration did not enhance the anti-inflammatory efficacy of the micellar extract compared to the native extract in this ex vivo model.
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Affiliation(s)
- Michael Schmiech
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University, Helmholtzstr. 20, Ulm 89081, Germany
| | - Emaad Abdel-Kahaar
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University, Helmholtzstr. 20, Ulm 89081, Germany
| | - Judith Ulrich
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University, Helmholtzstr. 20, Ulm 89081, Germany
| | - Maximilian Pfeiffer
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University, Helmholtzstr. 20, Ulm 89081, Germany
| | - Amira Duweb
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University, Helmholtzstr. 20, Ulm 89081, Germany; Department of Pharmacology, Faculty of Medicine, University of Tripoli, Tripoli 13628, Libya
| | - Oliver Zolk
- Institute of Clinical Pharmacology, Brandenburg Medical School, Immanuel Hospital Rüdersdorf, Rüdersdorf 15562, Germany
| | - Tatiana Syrovets
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University, Helmholtzstr. 20, Ulm 89081, Germany
| | - Thomas Simmet
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University, Helmholtzstr. 20, Ulm 89081, Germany.
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Pilotto Heming C, Muriithi W, Wanjiku Macharia L, Niemeyer Filho P, Moura-Neto V, Aran V. P-glycoprotein and cancer: what do we currently know? Heliyon 2022; 8:e11171. [PMID: 36325145 PMCID: PMC9618987 DOI: 10.1016/j.heliyon.2022.e11171] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022] Open
Abstract
Acquired resistance during cancer treatment is unfortunately a frequent event. There are several reasons for this, including the ability of the ATP-binding cassette transporters (ABC transporters), which are integral membrane proteins, to export chemotherapeutic molecules from the interior of the tumor cells. One important member of this family is the protein known as Permeability Glycoprotein (P-Glycoprotein, P-gp or ABCB1). Its clinical relevance relies mainly on the fact that the inhibition of P-gp and other ABC transporters could result in the reversal of the multidrug resistance (MDR) phenotype in some patients. Recently, other roles apart from being a key player in MDR, have emerged for P-gp. Therefore, this review discusses the relationship between P-gp and MDR, in addition to the possible role of this protein as a biomarker in cancer.
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Saeed MEM, Boulos JC, Machel K, Andabili N, Marouni T, Roth W, Efferth T. Expression of the Stem Cell Marker ABCB5 in Normal and Tumor Tissues. In Vivo 2022; 36:1651-1666. [PMID: 35738589 DOI: 10.21873/invivo.12877] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/05/2022] [Accepted: 04/12/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND/AIM The ATP-binding cassette subfamily B member 5 (ABCB5) transporter plays a pivotal role in melanocyte progenitor cell fusion and has been identified as a tumor-initiating cell marker. In this study, we determined ABCB5 expression in normal tissues among various species, i.e., Homo sapiens, Mus musculus (mouse), Rattus norvegicus (rat), Sus scrofa domesticus (pig), Gallus gallus (chicken), Anser anser (goose), Poecilia reticulata (Guppy fish), and Lumbricus terrestris (earthworm), as well as 426 biopsies of different human tumor types (colorectal, cervical, endometrium, vaginal, nasopharyngeal, kidney, breast, colon, prostate, pancreas, lung, gallbladder, bladder, brain, liver, skin, small intestine, testis, tonsil, uterus, thyroid, stomach, esophagus, fallopian, parotid, and ovary). MATERIALS AND METHODS Using immunohistochemical staining, ABCB5 expression was detected and evaluated in formalin-fixed, paraffin-embedded sections. RESULTS High ABCB5 expression was found in normal tissues in specialized cells with secretory and excretory functions, chorionic villi of the placenta, hepatocytes, and blood-tissue barrier sites in the brain and testis. Besides, heterogeneous expression of ABCB5 was also observed in many different tumor types derived from breast, endometrium, ovary, uterus, cervix, prostate, lung, brain, colon, liver, nasopharynx, and others. CONCLUSION The localization of ABCB5 in different normal tissues suggests that this protein has an excretory pumping role for physiological metabolites and xenobiotics. This physiological role highlighted its possible impact on the development of multidrug resistance in tumors. Further studies are required to establish the possible clinical significance of ABCB5 as a predictive marker for drug resistance and as a prognostic marker for patient survival.
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Affiliation(s)
- Mohamed E M Saeed
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Joelle C Boulos
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Kevin Machel
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Nasim Andabili
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Thamail Marouni
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Wilfried Roth
- Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany;
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Kumar R, Yadav N, Jain H, Deswal N, Upadhyay RK, Leekha A, Verma AK, Kareem A, Chikati R, Kumar LS. Microwave‐Assisted Synthesis of 4‐Aryl‐1,4‐dihydropyridines as Potent Anticancer Agent and Their
In‐Silico Studies. ChemistrySelect 2022. [DOI: 10.1002/slct.202104129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Rakesh Kumar
- Bioorganic Laboratory Department of Chemistry University of Delhi Delhi 110007 India
| | - Neha Yadav
- Bioorganic Laboratory Department of Chemistry University of Delhi Delhi 110007 India
| | - Harshita Jain
- Bioorganic Laboratory Department of Chemistry University of Delhi Delhi 110007 India
| | - Nidhi Deswal
- Bioorganic Laboratory Department of Chemistry University of Delhi Delhi 110007 India
| | | | - Ankita Leekha
- Nano Biotech Laboratory Department of Zoology Kirori Mal College University of Delhi Delhi 110007 India
| | - Anita Kamra Verma
- Nano Biotech Laboratory Department of Zoology Kirori Mal College University of Delhi Delhi 110007 India
| | | | - Rajasekhar Chikati
- Department of Biochemistry Yogivemana University Kadpa- 516005 Andhra Pradesh India
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Whyte-Allman SK, Bendayan R. HIV-1 Sanctuary Sites-the Role of Membrane-Associated Drug Transporters and Drug Metabolic Enzymes. AAPS JOURNAL 2020; 22:118. [PMID: 32875457 DOI: 10.1208/s12248-020-00498-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 08/06/2020] [Indexed: 02/08/2023]
Abstract
Despite significant advances in the treatment of human immunodeficiency virus-1 (HIV) infection with highly active antiretroviral drug therapy, the persistence of the virus in cellular and anatomic reservoirs is a major obstacle preventing total HIV eradication. Viral persistence could result from a variety of contributing factors including, but not limited to, non-adherence to treatment and adverse drug reactions, latently infected cells carrying replication-competent virus, drug-drug interactions, and inadequate antiretroviral drug (ARV) concentrations reached in several anatomic sites such as the brain, testis, and gut-associated lymphoid tissues. The distribution of ARVs at specific sites of infection is primarily dependent on drug physicochemical properties and drug plasma protein binding, as well as drug efflux, influx, and metabolic processes. A thorough understanding of the functional roles of drug transporters and metabolic enzymes in the disposition of ARVs in immune cell types and tissues that are characterized as HIV reservoirs and sanctuaries is critical to overcome the challenge of suboptimal drug distribution at sites of persistent HIV infection. This review summarizes the current knowledge related to the expression and function of drug transporters and metabolic enzymes in HIV cellular and anatomic reservoirs, and their potential contribution to drug-drug interactions and insufficient drug concentration at these sites.
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Affiliation(s)
- Sana-Kay Whyte-Allman
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada
| | - Reina Bendayan
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
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Bossennec M, Di Roio A, Caux C, Ménétrier-Caux C. MDR1 in immunity: friend or foe? Oncoimmunology 2018; 7:e1499388. [PMID: 30524890 PMCID: PMC6279327 DOI: 10.1080/2162402x.2018.1499388] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 07/08/2018] [Indexed: 02/09/2023] Open
Abstract
MDR1 is an ATP-dependent transmembrane transporter primarily studied for its role in the detoxification of tissues and for its implication in resistance of tumor cells to chemotherapy treatment. Several studies also report on its expression on immune cells where it plays a protective role from xenobiotics and toxins. This review provides an overview of what is known on MDR1 expression in immune cells in human, and its implications in different pathologies and their treatment options.
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Affiliation(s)
- Marion Bossennec
- Centre Léon Bérard, Cancer Research Center of Lyon (CRCL), Univ Lyon, Université Claude Bernard Lyon 1, Lyon France.,Immunology Virology Inflammation (IVI) department, Team "Therapeutic targeting of the tumor cells and their immune stroma", Lyon, France
| | - Anthony Di Roio
- Centre Léon Bérard, Cancer Research Center of Lyon (CRCL), Univ Lyon, Université Claude Bernard Lyon 1, Lyon France.,Immunology Virology Inflammation (IVI) department, Team "Therapeutic targeting of the tumor cells and their immune stroma", Lyon, France
| | - Christophe Caux
- Centre Léon Bérard, Cancer Research Center of Lyon (CRCL), Univ Lyon, Université Claude Bernard Lyon 1, Lyon France.,Immunology Virology Inflammation (IVI) department, Team "Therapeutic targeting of the tumor cells and their immune stroma", Lyon, France
| | - Christine Ménétrier-Caux
- Centre Léon Bérard, Cancer Research Center of Lyon (CRCL), Univ Lyon, Université Claude Bernard Lyon 1, Lyon France.,Immunology Virology Inflammation (IVI) department, Team "Therapeutic targeting of the tumor cells and their immune stroma", Lyon, France
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Goto RN, Sobral LM, Sousa LO, Garcia CB, Lopes NP, Marín-Prida J, Ochoa-Rodríguez E, Verdecia-Reyes Y, Pardo-Andreu GL, Curti C, Leopoldino AM. Anti-cancer activity of a new dihydropyridine derivative, VdiE-2N, in head and neck squamous cell carcinoma. Eur J Pharmacol 2018; 819:198-206. [DOI: 10.1016/j.ejphar.2017.12.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 12/02/2017] [Accepted: 12/04/2017] [Indexed: 12/16/2022]
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Li X, Lu J, Kan Q, Li X, Fan Q, Li Y, Huang R, Slipicevic A, Dong HP, Eide L, Wang J, Zhang H, Berge V, Goscinski MA, Kvalheim G, Nesland JM, Suo Z. Metabolic reprogramming is associated with flavopiridol resistance in prostate cancer DU145 cells. Sci Rep 2017; 7:5081. [PMID: 28698547 PMCID: PMC5506068 DOI: 10.1038/s41598-017-05086-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 05/24/2017] [Indexed: 01/19/2023] Open
Abstract
Flavopiridol (FP) is a pan-cyclin dependent kinase inhibitor, which shows strong efficacy in inducing cancer cell apoptosis. Although FP is potent against most cancer cells in vitro, unfortunately it proved less efficacious in clinical trials in various aggressive cancers. To date, the molecular mechanisms of the FP resistance are mostly unknown. Here, we report that a small fraction human prostate cancer DU145 cells can survive long-term FP treatment and emerge as FP-resistant cells (DU145FP). These DU145FP cells show accumulated mitochondrial lesions with stronger glycolytic features, and they proliferate in slow-cycling and behave highly migratory with strong anti-apoptotic potential. In addition, the cells are less sensitive to cisplatin and docetaxel-induced apoptotic pressure, and over-express multiple stem cell associated biomarkers. Our studies collectively uncover for the first time that FP-resistant prostate cancer cells show metabolic remodeling, and the metabolic plasticity might be required for the FP resistance-associated cancer cell stemness up-regulation.
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Affiliation(s)
- Xiaoran Li
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway
- Department of Pathology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0318, Norway
| | - Jie Lu
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Quancheng Kan
- Department of Clinical Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Xiaoli Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Qiong Fan
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, 0316, Norway
| | - Yaqing Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Ruixia Huang
- Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway
| | - Ana Slipicevic
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway
| | - Hiep Phuc Dong
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway
| | - Lars Eide
- Department of Medical Biochemistry, University of Oslo and Oslo University Hospital, Oslo, 0372, Norway
| | - Junbai Wang
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway
| | - Hongquan Zhang
- Laboratory of Molecular Cell Biology and Tumor Biology, Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, 100191, China
| | - Viktor Berge
- Department of Urology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway
| | - Mariusz Adam Goscinski
- Departments of Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0379, Norway
| | - Gunnar Kvalheim
- Department of Cell Therapy, Cancer Institute, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway
| | - Jahn M Nesland
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway
- Department of Pathology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0318, Norway
| | - Zhenhe Suo
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0379, Norway.
- Department of Pathology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0318, Norway.
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Fardel O, Le Vee M, Jouan E, Denizot C, Parmentier Y. Nature and uses of fluorescent dyes for drug transporter studies. Expert Opin Drug Metab Toxicol 2015; 11:1233-51. [PMID: 26050735 DOI: 10.1517/17425255.2015.1053462] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Drug transporters are now recognized as major players involved in pharmacokinetics and toxicology. Methods for assessing their activity are important to consider, particularly owing to regulatory requirements with respect to inhibition of drug transporter activity and prediction of drug-drug interactions. In this context, the use of fluorescent-dye-based transport assays is likely to deserve attention. AREAS COVERED This review provides an overview of the nature of fluorescent dye substrates for ATP-binding cassette and solute carrier drug transporters. Their use for investigating drug transporter activity in cultured cells and clinical hematological samples, drug transporter inhibition, drug transporter imaging and drug transport at the organ level are summarized. EXPERT OPINION A wide range of fluorescent dyes is now available for use in various aspects of drug transporter studies. The use of these dyes for transporter analyses may, however, be hampered by classic pitfalls of fluorescence technology, such as quenching. Transporter-independent processes such as passive diffusion of dyes through plasma membrane or dye sequestration into subcellular compartments must also be considered, as well as the redundant handling by various distinct transporters of some fluorescent probes. Finally, standardization of dye-based transport assays remains an important on-going issue.
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Affiliation(s)
- Olivier Fardel
- Institut de Recherches en Santé, Environnement et Travail (IRSET) , UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes , France
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Shekari F, Sadeghpour H, Javidnia K, Saso L, Nazari F, Firuzi O, Miri R. Cytotoxic and multidrug resistance reversal activities of novel 1,4-dihydropyridines against human cancer cells. Eur J Pharmacol 2015; 746:233-44. [DOI: 10.1016/j.ejphar.2014.10.058] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 10/26/2014] [Accepted: 10/27/2014] [Indexed: 10/24/2022]
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Jin JO, Zhang W, Wong KW, Kwak M, van Driel IR, Yu Q. Inhibition of breast cancer resistance protein (ABCG2) in human myeloid dendritic cells induces potent tolerogenic functions during LPS stimulation. PLoS One 2014; 9:e104753. [PMID: 25111504 PMCID: PMC4128747 DOI: 10.1371/journal.pone.0104753] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 07/15/2014] [Indexed: 02/04/2023] Open
Abstract
Breast cancer resistance protein (ABCG2), a member of the ATP-binding cassette transporters has been identified as a major determinant of multidrug resistance (MDR) in cancer cells, but ABC transporter inhibition has limited therapeutic value in vivo. In this research, we demonstrated that inhibition of efflux transporters ABCG2 induced the generation of tolerogenic DCs from human peripheral blood myeloid DCs (mDCs). ABCG2 expression was present in mDCs and was further increased by LPS stimulation. Treatment of CD1c+ mDCs with an ABCG2 inhibitor, Ko143, during LPS stimulation caused increased production of IL-10 and decreased production of pro-inflammatory cytokines and decreased expression of CD83 and CD86. Moreover, inhibition of ABCG2 in monocyte-derived DCs (MDDCs) abrogated the up-regulation of co-stimulatory molecules and production of pro-inflammatory cytokines in these cells in response to LPS. Furthermore, CD1c+ mDCs stimulated with LPS plus Ko143 inhibited the proliferation of allogeneic and superantigen-specific syngenic CD4+ T cells and promoted expansion of CD25+FOXP3+ regulatory T (Treg) cells in an IL-10-dependent fashion. These tolerogenic effects of ABCG2 inhibition could be abolished by ERK inhibition. Thus, we demonstrated that inhibition of ABCG2 in LPS-stimulated mDCs can potently induce tolerogenic potentials in these cells, providing crucial new information that could lead to development of better strategies to combat MDR cancer.
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Affiliation(s)
- Jun-O Jin
- Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China
- * E-mail:
| | - Wei Zhang
- Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ka-Wing Wong
- Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Minseok Kwak
- Department of Chemistry, Pukyong National University, Busan, South Korea
| | - Ian R. van Driel
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia
| | - Qing Yu
- Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, Massachusetts, United States of America
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Inui N, Hasegawa H, Suda T, Nakamura Y, Watanabe H, Chida K. Expression and Function of Multidrug Resistance Protein 1 and Multidrug Resistance-Associated Protein 1 in Lung Dendritic Cells From Aging Mice. J Gerontol A Biol Sci Med Sci 2012; 67:1049-55. [DOI: 10.1093/gerona/gls069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
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Hasegawa H, Inui N, Suda T, Shibata K, Nakamura Y, Watanabe H, Nakamura H, Chida K. Expressions of multidrug resistance protein 1 and multidrug resistance-associated protein 1 in lung dendritic cells. Life Sci 2011; 89:282-7. [DOI: 10.1016/j.lfs.2011.06.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 05/31/2011] [Accepted: 06/14/2011] [Indexed: 01/11/2023]
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Ven R, Lindenberg JJ, Reurs AW, Scheper RJ, Scheffer GL, Gruijl TD. Preferential Langerhans cell differentiation from CD34
+
precursors upon introduction of ABCG2 (BCRP). Immunol Cell Biol 2011; 90:206-15. [DOI: 10.1038/icb.2011.25] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Rieneke Ven
- Department of Pathology, VU University Medical Center Amsterdam The Netherlands
- Department of Medical Oncology, VU University Medical Center Amsterdam The Netherlands
| | - Jelle J Lindenberg
- Department of Medical Oncology, VU University Medical Center Amsterdam The Netherlands
| | - Anneke W Reurs
- Department of Pathology, VU University Medical Center Amsterdam The Netherlands
| | - Rik J Scheper
- Department of Pathology, VU University Medical Center Amsterdam The Netherlands
| | - George L Scheffer
- Department of Pathology, VU University Medical Center Amsterdam The Netherlands
| | - Tanja D Gruijl
- Department of Medical Oncology, VU University Medical Center Amsterdam The Netherlands
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Moreau A, Le Vee M, Jouan E, Parmentier Y, Fardel O. Drug transporter expression in human macrophages. Fundam Clin Pharmacol 2011; 25:743-52. [PMID: 21210849 DOI: 10.1111/j.1472-8206.2010.00913.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Macrophages represent major cellular targets of various drugs, especially antibiotics and anti-viral drugs. Factors that may govern intracellular accumulation of drugs in these cells, especially those related to activity of drug transporters, are consequently likely important to consider. The present study was therefore designed to extensively characterize expression of solute carrier (SLC) and ATP-binding cassette (ABC) transporters in primary human macrophages generated from blood monocytes. Using quantitative polymerase chain reaction assays, these cells were found to exhibit very high or high levels of mRNA expression of concentrative nucleoside transporter (CNT) 3, equilibrative nucleoside transporter 3, monocarboxylate transporter (MCT) 1, MCT4, peptide/histidine transporter (PHT) 1, PHT2, organic anion transporting polypeptide transporter 2B1 and ABC pumps multidrug resistance protein (MRP) 1/ABCC1 and MRP3/ABCC3. By contrast, other transporters, including the efflux pump ABCB1/P-glycoprotein, were found at lower levels or were not expressed. Concomitantly, human macrophages displayed notable uptake of the MCT substrate lactate and of the CNT substrate uridine and also exhibited cellular efflux of the MRP substrate carboxy-2',7'-dichlorofluorescein. Such a functional expression of these transporters has likely to be considered with respect to cellular pharmacokinetics of drugs targeting macrophages.
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Affiliation(s)
- Amélie Moreau
- EA 4427 Signalisation et Réponse aux Agents Infectieux et Chimiques, Institut de Recherches en Santé, Environnement et Travail, Université de Rennes 1, 2 avenue du Pr Léon Bernard, 35043 Rennes, France
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Munić V, Kelnerić Z, Mikac L, Eraković Haber V. Differences in assessment of macrolide interaction with human MDR1 (ABCB1, P-gp) using rhodamine-123 efflux, ATPase activity and cellular accumulation assays. Eur J Pharm Sci 2010; 41:86-95. [PMID: 20621639 DOI: 10.1016/j.ejps.2010.05.016] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2010] [Revised: 05/19/2010] [Accepted: 05/30/2010] [Indexed: 11/16/2022]
Abstract
In this study five macrolide antibiotics (azithromycin, erythromycin, clarithromycin, roxithromycin and telithromycin) were compared based on their ability to interact with human MDR1 (ABCB1, P-glycoprotein), studied from two main aspects: by determining the influence of macrolide antibiotics on MDR1 function, as well as the influence of MDR1 on macrolide accumulation in MES-SA/Dx5 cells overexpressing human MDR1. At higher micromolar concentrations five tested macrolides were shown to inhibit MDR1 function in terms of rhodamine-123 efflux and verapamil-activated ATPase function, whereas at lower concentrations they activated MDR1 ATPase. They were confirmed to be substrates of MDR1 and to compete with each other, as well as with verapamil for transport via this transporter. Expression of MDR1 on cells decreased macrolide accumulation in cells from 2- to 80-fold with the most pronounced change observed for azithromycin and erythromycin. Moreover, presence of active MDR1 highly affected the relative ranking of tested macrolides according to their accumulation in cells. In conclusion, out of seven applied methods and assessed parameters, four of them gave similar rough evaluation on the strength of interaction of five macrolides with MDR1, with clarithromycin, roxithromycin and telithromycin showing stronger interaction than azithromycin and erythromycin.
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Affiliation(s)
- Vesna Munić
- GlaxoSmithKline Research Centre Zagreb Ltd, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
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van de Ven R, Oerlemans R, van der Heijden JW, Scheffer GL, de Gruijl TD, Jansen G, Scheper RJ. ABC drug transporters and immunity: novel therapeutic targets in autoimmunity and cancer. J Leukoc Biol 2009; 86:1075-87. [PMID: 19745159 DOI: 10.1189/jlb.0309147] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
ABC transporters were identified originally for their contribution to clinical MDR as a result of their capacity to extrude various unrelated cytotoxic drugs. More recent reports have shown that ABC transporters can play important roles in the development, differentiation, and maturation of immune cells and are involved in migration of immune effector cells to sites of inflammation. Many of the currently identified, endogenous ABC transporter substrates have immunostimulating effects. Increasing the expression of ABC transporters on immune cells and thereby enhancing immune cell development or functionality may be beneficial to immunotherapy in the field of oncology. On the contrary, in the treatment of autoimmune diseases, blockade of these transporters may prove beneficial, as it could dampen disease activity by compromising immune effector cell functions. This review will focus on the expression, regulation, and substrate specificity of ABC transporters in relation to functional activities of immune effector cells and discusses implications for the treatment of cancer on the one hand and autoimmune diseases on the other.
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Affiliation(s)
- Rieneke van de Ven
- Department of Pathology, VU University Medical Center/Cancer Center Amsterdam, Amsterdam, Zuid Holland 1081 HV The Netherlands
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18
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The ABC of dendritic cell development and function. Trends Immunol 2009; 30:421-9. [PMID: 19699682 DOI: 10.1016/j.it.2009.06.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2009] [Revised: 06/24/2009] [Accepted: 06/25/2009] [Indexed: 12/14/2022]
Abstract
ATP-binding cassette (ABC) transporters are known for their involvement in clinical multidrug resistance (MDR) and their physiological defensive functions in barrier organs. More recently, attention has been focused on their possible involvement in the regulation of immune responses following the identification of their substrates as known immunomodulating agents (e.g. prostaglandins, leukotrienes and cyclic nucleotides) and their functional expression in various immune effector cells, most notably in dendritic cells (DCs). This review addresses the possible roles of ABC transporters in DC development and function, as well as the putative immunostimulatory potential of their cytostatic substrates and how this knowledge might benefit DC-based chemo-immunotherapies.
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Ishri RK, Menzies S, Halliday GM. Verapamil Induces Upregulation of P-glycoprotein Expression on Human Monocyte Derived Dendritic Cells. Immunol Invest 2009; 35:1-18. [PMID: 16531326 DOI: 10.1080/08820130500496746] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Overexpression of P-glycoprotein, a transmembrane drug efflux pump that mediates efflux of chemotherapeutic agents contributes to drug resistance in many leukaemia and other cancerous cells. Non-malignant cells including leukocytes also express P-glycoprotein, but physiologic functions for P-glycoprotein are poorly defined. Recently, P-glycoprotein expression has been described in human mononuclear phagocytes and Langerhans cells. It has been shown to play a role in phagocytic cell transmigration through endothelial-lined vessels in an ablumenal-lumenal direction, a process that mimics their migration into lymphatic vessels. Using the monoclonal antibody 4E3, and the P-glycoprotein antagonist, verapamil, the expression of P-glycoprotein on human monocyte-derived dendritic cells was evaluated. Dendritic cells used in this study were CD1a+, CD11c+, CD14-, CD80+, CD83+, CD86+ and MHC-II(High). The expression of these markers increased significantly as the cells matured. P-glycoprotein expression was upregulated as the dendritic cells matured as well as in the presence of the "inflammatory stress" of the pathogenic bacteria Strept. pyogenes. Addition of verapamil or Strept. pyogenes to the culture medium during the final 24 hours significantly upregulated P-glycoprotein expression. Immortalized cell lines did not upregulate P-glycoprotein in the presence of verapamil. Evaluation of other normal cells showed that P-glycoprotein upregulation in the presence of verapamil was also a characteristic of macrophages. This novel observation of the upregulation of P-glycoprotein in the presence of verapamil appears to be a characteristic of activated myeloid derived antigen presenting cells and suggest that P-glycoprotein is essential for these cells as when it is blocked, they respond by increasing expression of this protein. In summary, this work describes that human dendritic cells generated from plastic-adherent monocytes rapidly upregulate expression of P-glycoprotein as they mature, and in the presence of inflammatory stress and the pharmacological agent verapamil, which blocks P-glycoprotein activity, suggesting that P-glycoprotein may play a role in activation as well as in migration of dendritic cells.
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Affiliation(s)
- Raj K Ishri
- Dermatology Laboratories, Melanoma and Skin Cancer Research Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital at University of Sydney, Sydney, NSW, Australia
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Kyle-Cezar F, Echevarria-Lima J, Rumjanek VM. Independent Regulation of ABCB1 and ABCC Activities in Thymocytes and Bone Marrow Mononuclear Cells during Aging. Scand J Immunol 2007; 66:238-48. [PMID: 17635801 DOI: 10.1111/j.1365-3083.2007.01965.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Aging modifies a number of functional and phenotypic parameters of cells from the immune system. In this study, the activities of two members of the superfamily of ATP-binding cassette (ABC) transport proteins, ABCB1 and ABCC (measured by rhodamine 123 efflux and Fluo-3 efflux respectively), were compared in murine bone marrow cells and thymocytes of young (3-4 weeks old), adult (2-3 months old) and old (18 months old) mice. ABCB1 activity was shown to be age regulated in murine bone marrow mononuclear cells and thymocytes. In the bone marrow, the increased amount of cells with ABCB1 activity observed in old mice was restricted to the c-kit(-)Sca-1(+) and c-kit(+)Sca-1(+) subpopulations. Only a small percentage of c-kit(+) cells in the thymus had ABCB1 activity, and this subpopulation increased with age. In the thymus, old age augmented this activity in the CD4(-) CD8(-) double-negative cells and in the CD4(+) and CD8(+) single-positive populations. The activity of another ABC transporter, the ABCC-related activity, was also modified by age in the bone marrow. However, the age-related increase was observed in the subpopulations were ABCB1 was not modified, namely the non-progenitor population (c-kit(-)Sca-1(-)cells) and c-kit(+)Sca-1(-) cells. Nearly, all thymocytes expressed the ABCC1 molecule in an active form and aging did not affect this pattern. This study demonstrates an independent upregulation of ABCB1 and ABCC activities during the aging process. The increases were observed in different subsets of cells but followed a developmentally regulated pattern. The functions played by these transporters and alterations in aging are discussed.
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Affiliation(s)
- F Kyle-Cezar
- Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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van de Ven R, de Jong MC, Reurs AW, Schoonderwoerd AJN, Jansen G, Hooijberg JH, Scheffer GL, de Gruijl TD, Scheper RJ. Dendritic Cells Require Multidrug Resistance Protein 1 (ABCC1) Transporter Activity for Differentiation. THE JOURNAL OF IMMUNOLOGY 2006; 176:5191-8. [PMID: 16621983 DOI: 10.4049/jimmunol.176.9.5191] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Dendritic cells (DC) express the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and multidrug resistance protein 1 (MRP1; ABCC1). Functionally, both these transporters have been described to be required for efficient DC and T cell migration. In this study, we report that MRP1 activity is also crucial for differentiation of DC. Inhibition of MRP1, but not P-glycoprotein, transporter activity with specific antagonists during in vitro DC differentiation interfered with early DC development. Impaired interstitial and Langerhans DC differentiation was characterized by 1) morphological changes, reflected by dropped side scatter levels in flow cytometric analysis and 2) phenotypic changes illustrated by maintained expression of the monocytic marker CD14, lower expression levels of CD40, CD86, HLA-DR, and a significant decrease in the amount of cells expressing CD1a, CD1c, and Langerin. Defective DC differentiation also resulted in their reduced ability to stimulate allogeneic T cells. We identified the endogenous CD1 ligands sulfatide and monosialoganglioside GM1 as MRP1 substrates, but exogenous addition of these substrates could not restore the defects caused by blocking MRP1 activity during DC differentiation. Although leukotriene C(4) was reported to restore migration of murine Mrp1-deficient DC, the effects of MRP1 inhibition on DC differentiation appeared to be independent of the leukotriene pathway. Though MRP1 transporter activity is important for DC differentiation, the relevant MRP1 substrate, which is required for DC differentiation, remains to be identified. Altogether, MRP1 seems to fulfill an important physiological role in DC development and DC functions.
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Affiliation(s)
- Rieneke van de Ven
- Department of Pathology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
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Zhang J, Alston MA, Huang H, Rabin RL. Human T cell cytokine responses are dependent on multidrug resistance protein-1. Int Immunol 2006; 18:485-93. [PMID: 16481346 DOI: 10.1093/intimm/dxh389] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Multidrug resistance protein-1 (MRP1) belongs to subfamily C of the ATP-binding cassette transporters, and exports leukotriene C(4) and organic anions including the fluorescent calcium indicator indo-1. The observation that leukocytes from patients with an autoimmune disease exported indo-1 at a higher rate than controls prompted the hypothesis that MRP1 contributes to the function of activated cells. To test this, we defined the expression of MRP1 on resting and activated human T cells, and determined whether T cell activation is dependent upon MRP1 function. MRP1 is expressed on resting memory but not on naive CD4 and CD8 T cells. After activation through the TCR, cord blood CD4 T cells express high levels of MRP1. Blockade of MRP1 with the specific inhibitor MK-571 abrogated superantigen-induced expression of IFN-gamma, tumor necrosis factor-alpha, IL-10, IL-2, IL-4 and CD69 by T cells without affecting their viability, and was reversible upon removal of MK-571 from the culture media. Electrophoretic mobility shift assays demonstrate that MRP1 blockade with MK-571 induces activation of the transcriptional repressor peroxisome proliferator-activated receptor-gamma in CD4 T cells, thus providing insight into the potential mechanism by which their responses are abrogated.
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Affiliation(s)
- Jinsong Zhang
- Center for Biologics Evaluation and Research, US Food and Drug Administration, Bethesda, MD 20892-4555, USA
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23
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Woodahl EL, Yang Z, Bui T, Shen DD, Ho RJY. MDR1 G1199A polymorphism alters permeability of HIV protease inhibitors across P-glycoprotein-expressing epithelial cells. AIDS 2005; 19:1617-25. [PMID: 16184031 DOI: 10.1097/01.aids.0000183626.74299.77] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVE To evaluate the impact of the human multidrug resistance gene (MDR1) G1199A polymorphism (amino acid change Ser400Asn) on P-glycoprotein (P-gp)-dependent transepithelial permeability and uptake kinetics of HIV protease inhibitors (PI), by using recombinant epithelial cells expressing wild-type MDR1 (MDR1wt) or the G1199A variant (MDR1(1199A)). METHODS Using a recombinant expression system developed previously, the transepithelial permeability and uptake kinetic parameters of five PI, amprenavir, indinavir, lopinavir, ritonavir, and saquinavir were estimated across polarized epithelial cells. RESULTS For all PI, the transepithelial permeability ratio (basolateral-to-apical transport divided by apical-to-basolateral transport) was significantly greater in MDR1(1199A) cells than MDR1wt cells: amprenavir (1.7-fold), indinavir (1.8-fold), lopinavir (1.5-fold), ritonavir (2.8-fold), and saquinavir (2.1-fold). However, the impact of G1199A on P-gp activity appeared to primarily influence drug permeability in the apical-to-basolateral direction. Kinetic analysis of ritonavir and saquinavir uptake by MDR1wt- and MDR1(1199A)-expressing cells showed that Vmax was similar, while uptake Km was significantly higher in cells expressing the G1199A variant suggesting that alterations in P-gp-dependent efflux mediated by G1199A were due to changes in transporter affinity. CONCLUSIONS Alterations in transepithelial permeability of HIV PI due to the G1199A polymorphism may impact oral bioavailability of PI and penetration into cells and tissues of the lymphoid and central nervous systems.
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Affiliation(s)
- Erica L Woodahl
- Department of Pharmaceutics, University of Washington, Seattle, Washington 98195-7610, USA
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Gogolák P, Réthi B, Hajas G, Rajnavölgyi E. Targeting dendritic cells for priming cellular immune responses. J Mol Recognit 2004; 16:299-317. [PMID: 14523943 DOI: 10.1002/jmr.650] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The cardinal role of dendritic cells (DC) in priming adaptive immunity and in orchestrating immune responses against all classes of pathogens and also against tumors is well established. Their unique potential both to maintain self-tolerance and to initiate protective immune responses against foreign and/or dangerous structures is based on the functional diversity and flexibility of these cells. Tissue DC lining antigenic portals such as mucosal surfaces and the skin are specialized to take up a wide array of compounds including proteins, lipids, carbohydrates, glycoproteins, glycolipids and oligonucleotides, particles carrying such structures and apoptotic or necrotic cells. This process is facilitated by specialized receptors with high endocytic capacity, which provides potential targets for delivering designed molecules. The best route for targeting B- and/or T cell epitopes, however, is still the subject of intense investigation. Immature DC, which reside in various tissues, can be activated by pathogens, stress and inflammation or modified metabolic products, which induce mobilization of cells to draining lymph nodes where they act as highly potent professional antigen presenting cells. This is brought about by the ability to present their accumulated intracellular content for both CD4+ helper (Th) and CD8+ cytotoxic/cytolytic T lymphocytes (Tc/CTL). Engulfed proteins are processed intracellularly and their peptide fragments are transported to the cell surface in the context of major histocompatibility complex encoded class I and II molecules for presentation to Th cells and CTLs, respectively. The T cell priming capacity of DC, however, depends not only on antigen presentation but also on other features of DC. Human monocyte-derived DC provide an excellent tool to study the internalizing, antigen-presenting and T cell-activating functions of DC at their immature and activated differentiation states. These biological activities of DC, however, are highly dependent on their migratory potential from the peripheral non-lymphoid tissues to the lymph nodes, on the expression of adhesion molecules, which support the interaction of DC with T lymphocytes, and the cytokines secreted by DC, which polarize immune responses to Th1-mediated cellular or Th2-mediated antibody responses. These results altogether demonstrate that monocyte-derived DC are useful candidates for in vitro or in vivo targeting of antigens to induce efficient adaptive immune responses against pathogens and also against tumors.
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Affiliation(s)
- Péter Gogolák
- Institute of Immunology, Faculty of Medicine, University of Debrecen, 98 Nagyerdei Blvd, Debrecen H-4012, Hungary
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Abstract
There is a great need for alternative experimental methods for measuring percutaneous xenobiotic biotransformation. Animal testing and excised human skin studies have been the historical standards for confirmation of therapeutic and toxic effects that occur in the skin as a result of drug and other chemical metabolism. Human skin epidermal bioequivalents have become progressively more used for these types of pharmacological/toxicological studies in recent years. These epidermal models have been used in the form of cell culture, tissue sheets, and highly differentiated epidermal and epidermal/dermal systems. This review highlights the existing published data on the utility of these skin bioequivalent models for various types of metabolism and toxicology studies that should be of interest to the dermatopharmaceutical scientist.
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Affiliation(s)
- Audra L Stinchcomb
- Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky Lexington, Kentucky 40536-0082, USA.
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Yang JY, Luo HY, Lin QY, Liu ZM, Yan LN, Lin P, Zhang J, Lei S. Subcellular daunorubicin distribution and its relation to multidrug resistance phenotype in drug-resistant cell line SMMC-7721/R. World J Gastroenterol 2002; 8:644-9. [PMID: 12174371 PMCID: PMC4656313 DOI: 10.3748/wjg.v8.i4.644] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the correlation between subcellular daunorubicin distribution and the multidrug resistance phenotype in drug-resistant cell line SMMC-7721/R.
METHODS: The multidrug resistant cell line SMMC-7721/R, a human hepatocellular carcinoma cell line, was established. Antisense oligonucleotides (AS-ODN) were used to obtain different multidrug resistance phenotypes by inhibiting the expression of mdr1 gene and/or multidrug resistance-related protein gene (mrp) using Lipofectamine as delivery agent. Expression of mdr1 and mrp genes was evaluated by RT-PCR and Western blotting. Intracellular daunorubicin (DNR) concentration was measured by flow cytometry. Subcellular DNR distribution was analyzed by confocal laser scanning microscopy. Adriamycin (ADM) and DNR sensitivity was examined by MTT method.
RESULTS: Low level expression of mdr1 and mrp mRNAs and no expression of P-Glycoprotein (P-gp) and multidrug resistance-related protein (P190) were detected in parental sensitive cells SMMC-7721/S, but over-expression of these two genes was observed in drug-resistant cell SMMC-7721/R. The expression of mdr1 and mrp genes in SMMC-7721/R cells was down-regulated to the level in the SMMC-7721/S cells by AS-ODN. Intracellular DNR concentration in SMMC-7721/S cells was 10 times higher than that in SMMC-7721/R cells. In SMMC7721/S cells intracellular DNR distributed evenly in the nucleus and cytoplasm, while in SMMC-7721/R cells DNR distributed in a punctate pattern in the cytoplasm and was reduced in the nucleus. DNR concentration in SMMC-7721/R cells co-transfected with AS-ODNs targeting to mdr1 and mrp mRNAs recovered to 25 percent of that in SMMC7721/S cells. Intracellular DNR distribution pattern in drug-resistant cells treated by AS-ODN was similar to drug-sensitive cell, and the cells resistance index (RI) to DNR and ADM decreased at most from 88.0 and 116.0 to 4.0 and 2.3, respectively. Co-Transfection of two AS-ODNs showed a stronger synergistic effect than separate transfection.
CONCLUSIONS: P-gp and P190 are two members mediating MDR in cell line SMMC7721/R. Intracellular drug concentration increase and subcellular distribution change are two important factors in multidrug resistance (MDR) formation. The second factor, drugs transport by P-gp and P190 from cell nucleus to organell in cytoplasm, may play a more important role.
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Affiliation(s)
- Jia-Yin Yang
- Department of General surgery, First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou 310003, China.
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Schroeijers AB, Reurs AW, Scheffer GL, Stam AGM, de Jong MC, Rustemeyer T, Wiemer EAC, de Gruijl TD, Scheper RJ. Up-regulation of drug resistance-related vaults during dendritic cell development. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 168:1572-8. [PMID: 11823484 DOI: 10.4049/jimmunol.168.4.1572] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
P-glycoprotein (Pgp) and vaults are associated with multidrug resistance in tumor cells, but their physiological functions are not yet clear. Pgp, the prototypical transmembrane transporter molecule, may also facilitate the migration of skin dendritic cells (DC). Vaults--ribonucleoprotein cell organelles, frequently overexpressed in Pgp-negative drug-resistant tumor cells--have also been associated with intracellular transport processes. Given the pivotal role of DC in dealing with exposure to potentially harmful substances, the present study was set out to examine the expression of Pgp and vaults during differentiation and maturation of DC. DC were obtained from different sources, including blood-derived monocytes, CD34(+) mononuclear cells, and chronic myeloid leukemia cells. Whereas flow cytometric and immunocytochemical analyses showed slightly augmented levels of Pgp, up-regulation of vault expression during DC culturing was strong, readily confirmed by Western blotting, and independent of the source of DC. In further exploring the functional significance of vault expression, it was found that supplementing DC cultures with polyclonal or mAbs against the major vault protein led to lower viabilities of LPS- or TNF-alpha-matured monocytes-DC. Moreover, expression of critical differentiation, maturation, and costimulatory molecules, including CD1a and CD83, was reduced and their capacity to induce Ag-specific T cell proliferative and IFN-gamma release responses was impaired. These data point to a role for vaults in both DC survival and functioning as APC.
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Affiliation(s)
- Anouk B Schroeijers
- Departments of. Pathology and Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
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