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Jorgensen C, Linville RM, Galea I, Lambden E, Vögele M, Chen C, Troendle EP, Ruggiu F, Ulmschneider MB, Schiøtt B, Lorenz CD. Permeability Benchmarking: Guidelines for Comparing in Silico, in Vitro, and in Vivo Measurements. J Chem Inf Model 2025; 65:1067-1084. [PMID: 39823383 DOI: 10.1021/acs.jcim.4c01815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Permeability is a measure of the degree to which cells can transport molecules across biological barriers. Units of permeability are distance per unit time (typically cm/s), where accurate measurements are needed to define drug delivery in homeostasis and to model dysfunction occurring during disease. This perspective offers a set of community-led guidelines to benchmark permeability data across multidisciplinary approaches and different biological contexts. First, we lay out the analytical framework for three methodologies to calculate permeability: in silico assays using either transition-based counting or the inhomogeneous-solubility diffusion approaches, in vitro permeability assays using cells cultured in 2D or 3D geometries, and in vivo assays utilizing in situ brain perfusion or multiple time-point regression analysis. Then, we demonstrate a systematic benchmarking of in silico to both in vitro and in vivo, depicting the ways in which each benchmarking is sensitive to the choices of assay design. Finally, we outline seven recommendations for best practices in permeability benchmarking and underscore the significance of tailored permeability assays in driving advancements in drug delivery research and development. Our exploration encompasses a discussion of "generic" and tissue-specific biological barriers, including the blood-brain barrier (BBB), which is a major hurdle for the delivery of therapeutic agents into the brain. By addressing challenges in reconciling simulated data with experimental assays, we aim to provide insights essential for optimizing accuracy and reliability in permeability modeling.
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Affiliation(s)
- Christian Jorgensen
- School of Medicine, Pharmacy and Biomedical Sciences, Faculty of Science & Health, University of Portsmouth, Portsmouth PO1 2DT, Hampshire, U.K
- Dept. of Chemistry, Aarhus University, Langelandsgade, 140 8000 Aarhus C, Denmark
| | - Raleigh M Linville
- The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, Massachusetts 02139, United States
| | - Ian Galea
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, U.K
| | - Edward Lambden
- Dept. of Chemistry, King's College London, London WC2R 2LS, U.K
| | - Martin Vögele
- Department of Computer Science, Stanford University, Stanford, California 94305, United States
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, California 94305, United States
- Institute for Computational and Mathematical Engineering, Stanford University, Stanford, California 94305, United States
| | - Charles Chen
- Synthetic Biology Group, Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Evan P Troendle
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, County Antrim, BT9 7BL, Northern Ireland, U.K
| | - Fiorella Ruggiu
- Kimia Therapeutics, 740 Heinz Avenue, Berkeley, California 94710, United States
| | | | - Birgit Schiøtt
- Dept. of Chemistry, Aarhus University, Langelandsgade, 140 8000 Aarhus C, Denmark
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Radhakrishnan A, Shanmukhan NK, Samuel LC. Pharmacogenomics influence on MDR1-associated cancer resistance and innovative drug delivery approaches: advancing precision oncology. Med Oncol 2025; 42:67. [PMID: 39913003 DOI: 10.1007/s12032-025-02611-w] [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: 11/08/2024] [Accepted: 01/15/2025] [Indexed: 02/07/2025]
Abstract
Currently, there is a growing concern surrounding the treatment of cancer, a formidable disease. Pharmacogenomics and personalized medicine have emerged as significant areas of interest in cancer management. The efficacy of many cancer drugs is hindered by resistance mechanisms, particularly P-glycoprotein (P-gp) efflux, leading to reduced therapeutic outcomes. Efforts have intensified to inhibit P-gp efflux, thereby enhancing the effectiveness of resistant drugs. P-gp, a member of the ATP-binding cassette (ABC) superfamily, specifically the multidrug resistance (MDR)/transporter associated with antigen processing (TAP) sub-family B, member 1, utilizes energy derived from ATP hydrolysis to drive efflux. This review focuses on genetic polymorphisms associated with P-gp efflux and explores various novel pharmaceutical strategies to address this challenge. These strategies encompass SEDDS/SNEDDS, liposomes, immunoliposomes, solid lipid nanoparticles, lipid core nanocapsules, microemulsions, dendrimers, hydrogels, polymer-drug conjugates, and polymeric nanoparticles. The article aims to elucidate the interplay between pharmacogenomics, P-gp-mediated drug resistance in cancer, and formulation strategies to improve cancer therapy by tailoring formulations to genetically susceptible patients.
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Affiliation(s)
- Arun Radhakrishnan
- Department of Pharmaceutics, JKKN College of Pharmacy, Kumarapalayam, Tamil Nadu, 638183, India.
| | - Nikhitha K Shanmukhan
- Department of Pharmaceutics, JKKN College of Pharmacy, Kumarapalayam, Tamil Nadu, 638183, India
| | - Linda Christabel Samuel
- Department of Conservative Dentistry and Endodontics, JKKN Dental College and Hospitals, Kumarapalayam, 638183, India
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3
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Phuna ZX, Kumar PA, Haroun E, Dutta D, Lim SH. Antibody-drug conjugates: Principles and opportunities. Life Sci 2024; 347:122676. [PMID: 38688384 DOI: 10.1016/j.lfs.2024.122676] [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: 02/14/2024] [Revised: 04/15/2024] [Accepted: 04/26/2024] [Indexed: 05/02/2024]
Abstract
Antibody-drug conjugates (ADCs) are immunoconjugates that combine the specificity of monoclonal antibodies with a cytotoxic agent. The most appealing aspects of ADCs include their potential additive or synergistic effects of the innate backbone antibody and cytotoxic effects of the payload on tumors without the severe toxic side effects often associated with traditional chemotherapy. Recent advances in identifying new targets with tumor-specific expression, along with improved bioactive payloads and novel linkers, have significantly expanded the scope and optimism for ADCs in cancer therapeutics. In this paper, we will first provide a brief overview of antibody specificity and the structure of ADCs. Next, we will discuss the mechanisms of action and the development of resistance to ADCs. Finally, we will explore opportunities for enhancing ADC efficacy, overcoming drug resistance, and offer future perspectives on leveraging ADCs to improve the outcome of ADC therapy for cancer treatment.
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Affiliation(s)
- Zhi Xin Phuna
- Research and Development, Medicovestor, Inc, New York City, NY, United States of America
| | - Prashanth Ashok Kumar
- Division of Hematology and Oncology, Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, United States of America
| | - Elio Haroun
- Division of Hematology and Oncology, Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, United States of America
| | - Dibyendu Dutta
- Division of Hematology and Oncology, Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, United States of America
| | - Seah H Lim
- Research and Development, Medicovestor, Inc, New York City, NY, United States of America; Division of Hematology and Oncology, Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, United States of America.
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Alshahrani SH, Yuliastanti T, Al-Dolaimy F, Korotkova NL, Rasulova I, Almuala AF, Alsaalamy A, Ali SHJ, Alasheqi MQ, Mustafa YF. A glimpse into let-7e roles in human disorders; friend or foe? Pathol Res Pract 2024; 253:154992. [PMID: 38103367 DOI: 10.1016/j.prp.2023.154992] [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: 10/15/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 12/19/2023]
Abstract
MicroRNAs (miRNAs) have been linked to abnormal expression and regulation in a number of diseases, including cancer. Recent studies have concentrated on miRNA Let-7e's significance in precision medicine for cancer screening and diagnosis as well as its prognostic and therapeutic potential. Differential let-7e levels in bodily fluids have the possibility to enable early detection of cancer utilizing less-invasive techniques, reducing biopsy-related risks. Although Let-7e miRNAs have been described as tumor suppressors, it is crucial to note that there exists proof to support their oncogenic activity in vitro and in in vivo. Let-7e's significance in chemo- and radiation treatment decisions has also been demonstrated. Let-7e can also prevent the synthesis of proinflammatory cytokines in a number of degenerative disorders, including musculoskeletal and neurological conditions. For the first time, an overview of the significance of let-7e in the prevention, detection, and therapy of cancer and other conditions has been given in the current review. Additionally, we focused on the specific molecular processes that underlie the actions of let-7e, more particularly, on malignant cells.
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Affiliation(s)
| | | | | | - Nadezhda L Korotkova
- I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation; Federal State Budgetary Educational Institution of Higher Education "Privolzhsky Research Medical University" of the Ministry of Health of the Russian Federation, Nizhny Novgorod, Russian Federation
| | - Irodakhon Rasulova
- School of Humanities, Natural & Social Sciences, New Uzbekistan University, 54 Mustaqillik Ave., Tashkent 100007, Uzbekistan; Department of Public Health, Samarkand State Medical University, Amir Temur Street 18, Samarkand, Uzbekistan
| | - Abbas Firras Almuala
- College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Iraq; College of Technical Engineering, the Islamic University of Babylon, Iraq
| | - Ali Alsaalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - Saad Hayif Jasim Ali
- Department of Medical Laboratory, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
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Gutay-Tóth Z, Gellen G, Doan M, Eliason JF, Vincze J, Szente L, Fenyvesi F, Goda K, Vecsernyés M, Szabó G, Bacso Z. Cholesterol-Depletion-Induced Membrane Repair Carries a Raft Conformer of P-Glycoprotein to the Cell Surface, Indicating Enhanced Cholesterol Trafficking in MDR Cells, Which Makes Them Resistant to Cholesterol Modifications. Int J Mol Sci 2023; 24:12335. [PMID: 37569709 PMCID: PMC10419235 DOI: 10.3390/ijms241512335] [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: 07/01/2023] [Revised: 07/26/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
The human P-glycoprotein (P-gp), a transporter responsible for multidrug resistance, is present in the plasma membrane's raft and non-raft domains. One specific conformation of P-gp that binds to the monoclonal antibody UIC2 is primarily associated with raft domains and displays heightened internalization in cells overexpressing P-gp, such as in NIH-3T3 MDR1 cells. Our primary objective was to investigate whether the trafficking of this particular P-gp conformer is dependent on cholesterol levels. Surprisingly, depleting cholesterol using cyclodextrin resulted in an unexpected increase in the proportion of raft-associated P-gp within the cell membrane, as determined by UIC2-reactive P-gp. This increase appears to be a compensatory response to cholesterol loss from the plasma membrane, whereby cholesterol-rich raft micro-domains are delivered to the cell surface through an augmented exocytosis process. Furthermore, this exocytotic event is found to be part of a complex trafficking mechanism involving lysosomal exocytosis, which contributes to membrane repair after cholesterol reduction induced by cyclodextrin treatment. Notably, cells overexpressing P-gp demonstrated higher total cellular cholesterol levels, an increased abundance of stable lysosomes, and more effective membrane repair following cholesterol modifications. These modifications encompassed exocytotic events that involved the transport of P-gp-carrying rafts. Importantly, the enhanced membrane repair capability resulted in a durable phenotype for MDR1 expressing cells, as evidenced by significantly improved viabilities of multidrug-resistant Pgp-overexpressing immortal NIH-3T3 MDR1 and MDCK-MDR1 cells compared to their parents when subjected to cholesterol alterations.
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Affiliation(s)
- Zsuzsanna Gutay-Tóth
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Gabriella Gellen
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
- MTA-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Department of Analytical Chemistry, Institute of Chemistry, ELTE Eötvös Loránd University, 1053 Budapest, Hungary
| | - Minh Doan
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
| | - James F. Eliason
- Great Lakes Stem Cell Innovation Center, Detroit, MI 48202, USA;
| | - János Vincze
- Department of Physiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Lajos Szente
- CycloLab Cyclodextrin Research & Development Laboratory, Ltd., 1097 Budapest, Hungary;
| | - Ferenc Fenyvesi
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary; (F.F.); (M.V.)
| | - Katalin Goda
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
| | - Miklós Vecsernyés
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary; (F.F.); (M.V.)
| | - Gábor Szabó
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
| | - Zsolt Bacso
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary; (F.F.); (M.V.)
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Turrini E, Maffei F, Fimognari C. Effect of the Marine Polyketide Plocabulin on Tumor Progression. Mar Drugs 2022; 21:md21010038. [PMID: 36662211 PMCID: PMC9860935 DOI: 10.3390/md21010038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 12/28/2022] [Accepted: 12/29/2022] [Indexed: 01/04/2023] Open
Abstract
Marine sponges represent one of the richest sources of natural marine compounds with anticancer potential. Plocabulin (PM060184), a polyketide originally isolated from the sponge Lithoplocamia lithistoides, elicits its main anticancer properties binding tubulin, which still represents one of the most important targets for anticancer drugs. Plocabulin showed potent antitumor activity, in both in vitro and in vivo models of different types of cancers, mediated not only by its antitubulin activity, but also by its ability to block endothelial cell migration and invasion. The objective of this review is to offer a description of plocabulin's mechanisms of action, with special emphasis on the antiangiogenic signals and the latest progress on its development as an anticancer agent.
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Apollonova VS, Sidina EI, Tkachenko EV, Malek AV. MicroRNA-dependent mechanisms of taxane resistance in breast cancer. TUMORS OF FEMALE REPRODUCTIVE SYSTEM 2022. [DOI: 10.17650/1994-4098-2022-18-3-52-63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Breast cancer (BC) has a leading position in the statistics of oncological morbidity and mortality among women. Taxan-based polychemotherapy regimens are an essential component of the complex therapy of the BC. However, currently used algorithms of taxan-based regimens application do not always provide with desire effect. It indicates the need to identify new prognostic markers and to develop new approaches to modify response of BC cells to standard therapeutic regimens. MicroRNAs, small RNA molecules regulating protein synthesis, are considered as promising markers and potential modulators of the BC cells sensitivity to taxanes.The review includes a brief summary of the molecular mechanisms of action of the taxanes and the mechanism BC resistance to the process of microtubules depolymerization, provides with analysis of recent experimental and observational studies of the role of microRNAs in control of these mechanisms, and evaluates prospects for the development of new approaches to predict and to improve the cytostatic effects of taxanes through the analysis and modification of cellular microRNAs.
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Affiliation(s)
- V. S. Apollonova
- N. N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia
| | - E. I. Sidina
- N. N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia
| | - E. V. Tkachenko
- N. N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia
| | - A. V. Malek
- N. N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia
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Kim SO, Kim BY, Lee KH. Synergistic effect of anticancer drug resistance and Wnt3a on primary ciliogenesis in A549 cell-derived anticancer drug-resistant subcell lines. Biochem Biophys Res Commun 2022; 635:1-11. [DOI: 10.1016/j.bbrc.2022.10.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 10/05/2022] [Indexed: 11/02/2022]
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Abdelaal MR, Ibrahim E, Elnagar MR, Soror SH, Haffez H. Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach. Int J Mol Sci 2022; 23:ijms23169442. [PMID: 36012706 PMCID: PMC9409216 DOI: 10.3390/ijms23169442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 07/29/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Colorectal cancer therapies have produced promising clinical responses, but tumor cells rapidly develop resistance to these drugs. It has been previously shown that EC19 and EC23, two EC-synthetic retinoids, have single-agent preclinical anticancer activity in colorectal carcinoma. Here, isobologram analysis revealed that they have synergistic cytotoxicity with retinoic acid receptor (RAR) isoform-selective agonistic retinoids such as AC261066 (RARβ2-selective agonist) and CD437 (RARγ-selective agonist) in Caco-2 cells. This synergism was confirmed by calculating the combination index (lower than 1) and the dose reduction index (higher than 1). Flow cytometry of combinatorial IC50 (the concentration causing 50% cell death) confirmed the cell cycle arrest at the SubG0-G1 phase with potentiated apoptotic and necrotic effects. The reported synergistic anticancer activity can be attributed to their ability to reduce the expression of ATP-binding cassette (ABC) transporters including P-glycoprotein (P-gp1), breast cancer resistance protein (BCRP) and multi-drug resistance-associated protein-1 (MRP1) and Heat Shock Protein 70 (Hsp70). This adds up to the apoptosis-promoting activity of EC19 and EC23, as shown by the increased Caspase-3/7 activities and DNA fragmentation leading to DNA double-strand breaks. This study sheds the light on the possible use of EC-synthetic retinoids in the rescue of multi-drug resistance in colorectal cancer using Caco-2 as a model and suggests new promising combinations between different synthetic retinoids. The current in vitro results pave the way for future studies on these compounds as possible cures for colorectal carcinoma.
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Affiliation(s)
- Mohamed R. Abdelaal
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt
- Center of Scientific Excellence “Helwan Structural Biology Research, (HSBR)”, Helwan University, Cairo 11795, Egypt
| | - Esraa Ibrahim
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt
- Center of Scientific Excellence “Helwan Structural Biology Research, (HSBR)”, Helwan University, Cairo 11795, Egypt
| | - Mohamed R. Elnagar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11823, Egypt
| | - Sameh H. Soror
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt
- Center of Scientific Excellence “Helwan Structural Biology Research, (HSBR)”, Helwan University, Cairo 11795, Egypt
| | - Hesham Haffez
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt
- Center of Scientific Excellence “Helwan Structural Biology Research, (HSBR)”, Helwan University, Cairo 11795, Egypt
- Correspondence: ; Tel.: +20-1094-970-173
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Disoma C, Zhou Y, Li S, Peng J, Xia Z. Wnt/β-catenin signaling in colorectal cancer: Is therapeutic targeting even possible? Biochimie 2022; 195:39-53. [DOI: 10.1016/j.biochi.2022.01.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 11/03/2021] [Accepted: 01/17/2022] [Indexed: 02/07/2023]
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Singh K, Tarapcsák S, Gyöngy Z, Ritter Z, Batta G, Bosire R, Remenyik J, Goda K. Effects of Polyphenols on P-Glycoprotein (ABCB1) Activity. Pharmaceutics 2021; 13:pharmaceutics13122062. [PMID: 34959345 PMCID: PMC8707248 DOI: 10.3390/pharmaceutics13122062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 11/09/2021] [Accepted: 11/26/2021] [Indexed: 11/17/2022] Open
Abstract
P-glycoprotein (Pgp, ABCB1) is a member of one of the largest families of active transporter proteins called ABC transporters. Thanks to its expression in tissues with barrier functions and its broad substrate spectrum, it is an important determinant of the absorption, metabolism and excretion of many drugs. Pgp and/or some other drug transporting ABC proteins (e.g., ABCG2, MRP1) are overexpressed in nearly all cancers and cancer stem cells by which cancer cells become resistant against many drugs. Thus, Pgp inhibition might be a strategy for fighting against drug-resistant cancer cells. Previous studies have shown that certain polyphenols interact with human Pgp. We tested the effect of 15 polyphenols of sour cherry origin on the basal and verapamil-stimulated ATPase activity of Pgp, calcein-AM and daunorubicin transport as well as on the conformation of Pgp using the conformation sensitive UIC2 mAb. We found that quercetin, quercetin-3-glucoside, narcissoside and ellagic acid inhibited the ATPase activity of Pgp and increased the accumulation of calcein and daunorubicin by Pgp-positive cells. Cyanidin-3O-sophoroside, catechin, naringenin, kuromanin and caffeic acid increased the ATPase activity of Pgp, while they had only a weaker effect on the intracellular accumulation of fluorescent Pgp substrates. Several tested polyphenols including epicatechin, trans-ferulic acid, oenin, malvin and chlorogenic acid were ineffective in all assays applied. Interestingly, catechin and epicatechin behave differently, although they are stereoisomers. We also investigated the effect of quercetin, naringenin and ellagic acid added in combination with verapamil on the transport activity of Pgp. In these experiments, we found that the transport inhibitory effect of the tested polyphenols and verapamil was additive or synergistic. Generally, our data demonstrate diverse interactions of the tested polyphenols with Pgp. Our results also call attention to the potential risks of drug–drug interactions (DDIs) associated with the consumption of dietary polyphenols concurrently with chemotherapy treatment involving Pgp substrate/inhibitor drugs.
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Affiliation(s)
- Kuljeet Singh
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Szabolcs Tarapcsák
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Utah Center for Genetic Discovery, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Zsuzsanna Gyöngy
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Zsuzsanna Ritter
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Gyula Batta
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Department of Genetics and Applied Microbiology, Faculty of Science of Technology, University of Debrecen, 4032 Debrecen, Hungary
| | - Rosevalentine Bosire
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Judit Remenyik
- Institute of Food Technology, Faculty of Agricultural and Food Sciences and Environmental Management, University of Debrecen, 4032 Debrecen, Hungary;
| | - Katalin Goda
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
- Correspondence:
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12
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Pajaniradje S, Mohankumar K, Radhakrishnan R, Sufi SA, Subramanian S, Anaikutti P, Hulluru SPR, Rajagopalan R. Indole Curcumin Reverses Multidrug Resistance by Reducing the Expression of ABCB1 and COX2 in Induced Multidrug Resistant Human Lung Cancer Cells. LETT DRUG DES DISCOV 2020. [DOI: 10.2174/1570180817666200402124503] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background:
Drug resistance by the cancer cells towards current chemotherapeutic
approaches poses a great challenge. In the present study, an indole analogue of a well-known plant
derived anticancer molecule, curcumin, was tested for its Multidrug Resistance (MDR) reversing
potential in induced multi drug resistant A549 cell line.
Materials and Methods:
Human lung cancer cell line A549 was made Multidrug Resistant (MDR)
by prolonged treatment with low dosage of Docetaxel, an established anticancer drug. The MDR
induction was confirmed by morphological evidence, Hoechst 33342 staining, MTT assay,
Rhodamine123 staining and RT-PCR of ABCB1 gene. Protein expression studies were carried out
using western blotting technique
Results and Discussions:
The induced MDR A549 cells exhibited significant increase in the gene
expression of ABCB1 gene at the transcriptional level. Retention and efflux studies with Pglycoprotein
(P-gp) substrate Rh123 indicated that indole curcumin inhibited P-gp mediated efflux
of Rhodamine. Furthermore, treatment of MDR A549 cells with indole curcumin showed downregulation
of gene expression of ABCB1 and COX 2. This was also confirmed from the decreased
protein expression of COX 2.
Conclusion:
The results of the present study indicate that indole curcumin reverses multi drug
resistance by downregulating the expression of ABCB1 and COX 2 genes. Thus, indole curcumin
may act as a potent modulator for ABCB1 and COX 2 mediated MDR in lung cancer.
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Affiliation(s)
- Sankar Pajaniradje
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry 605014, India
| | - Kumaravel Mohankumar
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry 605014, India
| | - Rakesh Radhakrishnan
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry 605014, India
| | - Shamim Akhtar Sufi
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry 605014, India
| | - Srividya Subramanian
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry 605014, India
| | | | | | - Rukkumani Rajagopalan
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry 605014, India
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13
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Enevoldsen FC, Sahana J, Wehland M, Grimm D, Infanger M, Krüger M. Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy. J Clin Med 2020; 9:jcm9030824. [PMID: 32197449 PMCID: PMC7141375 DOI: 10.3390/jcm9030824] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/13/2020] [Accepted: 03/16/2020] [Indexed: 02/06/2023] Open
Abstract
The endothelin axis, recognized for its vasoconstrictive action, plays a central role in the pathology of pulmonary arterial hypertension (PAH). Treatment with approved endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, or macitentan, slow down PAH progression and relieves symptoms. Several findings have indicated that endothelin is further involved in the pathogenesis of certain other diseases, making ERAs potentially beneficial in the treatment of various conditions. In addition to PAH, this review summarizes the use and perspectives of ERAs in cancer, renal disease, fibrotic disorders, systemic scleroderma, vasospasm, and pain management. Bosentan has proven to be effective in systemic sclerosis PAH and in decreasing the development of vasospasm-related digital ulcers. The selective ERA clazosentan has been shown to be effective in preventing cerebral vasospasm and delaying ischemic neurological deficits and new infarcts. Furthermore, in the SONAR (Study Of Diabetic Nephropathy With Atrasentan) trial, the selective ERA atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease. These data suggest atrasentan as a new therapy in the treatment of diabetic nephropathy and possibly other renal diseases. Preclinical studies regarding heart failure, cancer, and fibrotic diseases have demonstrated promising effects, but clinical trials have not yet produced measurable results. Nevertheless, the potential benefits of ERAs may not be fully realized.
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Affiliation(s)
- Frederik C. Enevoldsen
- Department of Biomedicine, Aarhus University, Høegh-Guldbergsgade 10, 8000 Aarhus C, Denmark; (F.C.E.); (J.S.); (D.G.)
| | - Jayashree Sahana
- Department of Biomedicine, Aarhus University, Høegh-Guldbergsgade 10, 8000 Aarhus C, Denmark; (F.C.E.); (J.S.); (D.G.)
| | - Markus Wehland
- Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany; (M.W.); (M.I.)
| | - Daniela Grimm
- Department of Biomedicine, Aarhus University, Høegh-Guldbergsgade 10, 8000 Aarhus C, Denmark; (F.C.E.); (J.S.); (D.G.)
- Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany; (M.W.); (M.I.)
| | - Manfred Infanger
- Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany; (M.W.); (M.I.)
| | - Marcus Krüger
- Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany; (M.W.); (M.I.)
- Correspondence: ; Tel.: +49-391-6721267
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14
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Interactions of Cisplatin and Daunorubicin at the Chromatin Level. Sci Rep 2020; 10:1107. [PMID: 31980698 PMCID: PMC6981277 DOI: 10.1038/s41598-020-57702-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 12/19/2019] [Indexed: 01/08/2023] Open
Abstract
Unexpectedly, the widely used anticancer agents Cisplatin (Cis-Pt) and Daunorubicin (Dauno) exhibited cell type- and concentration-dependent synergy or antagonism in vitro. We attempted to interpret these effects in terms of the changes elicited by the drugs in the chromatin, the target held primarily responsible for the cytotoxicity of both agents. We measured the effect of Cis-Pt on the levels of Dauno in different cell compartments, the effect of Cis-Pt on Dauno-induced nucleosome eviction, and assessed the influence of Dauno on DNA platination in flow- and laser scanning cytometry as well as in laser ablation-inductively coupled plasma-mass spectrometry assays. We show that the two drugs antagonize each other through a decrease of interstrand crosslinks upon co-treatment with Dauno, and also via the diminished Dauno uptake in the presence of Cis-Pt, and both effects are observed already at low Dauno concentrations. At high Dauno concentrations synergy becomes dominant because histone eviction by Dauno intercalation into the DNA is enhanced in the presence of co-treatment with Cis-Pt. These interactions may have an impact on the efficacy of combination treatment protocols, considering the long retention time of DNA adducts formed by both agents.
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15
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P-glycoprotein modulates oleanolic acid effects in hepatocytes cancer cells and zebrafish embryos. Chem Biol Interact 2020; 315:108892. [DOI: 10.1016/j.cbi.2019.108892] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 10/30/2019] [Accepted: 11/03/2019] [Indexed: 01/11/2023]
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16
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Cui Y, Lu C, Zhang Z, Mao A, Feng L, Fu L, Gu F, Ma X, He D. A Long Non-coding RNA Lnc712 Regulates Breast Cancer Cell Proliferation. Int J Biol Sci 2020; 16:162-171. [PMID: 31892853 PMCID: PMC6930380 DOI: 10.7150/ijbs.36429] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 07/29/2019] [Indexed: 12/22/2022] Open
Abstract
Great quantity of intergenic noncoding RNAs (lncRNAs) have been identified in the mammalian genome and involved in various biological processes, especially in the development and metastasis of cancer. In this study, we identified one lncRNA, lncRNA NONHSAT028712 (Lnc712), was highly expressed in breast cancer cell lines and tissues based on microarray screening. Knockdown of Lnc712 largely inhibited breast cancer cell proliferation. Mechanistically, Lnc712 bound specifically to heat-shock protein 90 (HSP90). Interaction between Lnc712 and HSP90 is required for HSP90 binding to cell division cycle 37 (Cdc37). The Lnc712/HSP90/Cdc37 complex regulated cyclin-dependent kinase 2 (CDK2) activation and then triggered breast cancer cell proliferation. In summary, our results identified a new lncRNA regulate breast cancer proliferation though interaction with HSP90.
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Affiliation(s)
- Yue Cui
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Chunxiao Lu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Zhiming Zhang
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Aiqin Mao
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Lei Feng
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Li Fu
- Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.,✉ Corresponding authors: Dongxu He, Ph.D. School of Food Science and Technology, Jiangnan University, Wuxi, China. ; Xin Ma, Ph.D. Wuxi School of Medicine, Jiangnan University, Wuxi, China. ; Feng Gu, M.D. Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China. ; Li Fu, M.D. Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
| | - Feng Gu
- Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.,✉ Corresponding authors: Dongxu He, Ph.D. School of Food Science and Technology, Jiangnan University, Wuxi, China. ; Xin Ma, Ph.D. Wuxi School of Medicine, Jiangnan University, Wuxi, China. ; Feng Gu, M.D. Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China. ; Li Fu, M.D. Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
| | - Xin Ma
- Wuxi School of Medicine, Jiangnan University, Wuxi, China.,✉ Corresponding authors: Dongxu He, Ph.D. School of Food Science and Technology, Jiangnan University, Wuxi, China. ; Xin Ma, Ph.D. Wuxi School of Medicine, Jiangnan University, Wuxi, China. ; Feng Gu, M.D. Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China. ; Li Fu, M.D. Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
| | - Dongxu He
- School of Food Science and Technology, Jiangnan University, Wuxi, China.,✉ Corresponding authors: Dongxu He, Ph.D. School of Food Science and Technology, Jiangnan University, Wuxi, China. ; Xin Ma, Ph.D. Wuxi School of Medicine, Jiangnan University, Wuxi, China. ; Feng Gu, M.D. Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China. ; Li Fu, M.D. Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
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17
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Knockdown of TM9SF4 boosts ER stress to trigger cell death of chemoresistant breast cancer cells. Oncogene 2019; 38:5778-5791. [PMID: 31249383 DOI: 10.1038/s41388-019-0846-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 02/02/2023]
Abstract
Drug resistance is one of the major obstacles to breast cancer therapy. However, the mechanisms of how cancer cells develop chemoresistance are still not fully understood. In the present study, we found that expression of TM9SF4 proteins was much higher in adriamycin (ADM)-resistant breast cancer cells MCF-7/ADM than in its parental line wild-type breast cancer cells MCF-7/WT. shRNA-mediated knockdown of TM9SF4 preferentially reduced cell growth and triggered cell death in chemoresistant MCF-7/ADM cells compared with MCF-7/WT cells. Knockdown of TM9SF4 also reduced cell growth and triggered cell death in chemoresistant MDA-MB-231/GEM cells. Mechanistic studies showed that TM9SF4 knockdown increased protein misfolding and elevated endoplasmic reticulum (ER) stress level in MCF-7/ADM cells, as indicated by aggresome formation and upregulated expression of ER stress markers, the effect of which was reversed by a small molecule chaperone 4-phenybutyric acid. In an athymic nude mouse model of ADM-resistant human breast xenograft tumor, knockdown of TM9SF4 decreased the growth of tumor xenografts. In chemoresistant breast cancer patients, chemotherapy increased the expression of TM9SF4 proteins in breast tumor samples. Taken together, these results uncovered a novel role of TM9SF4 proteins in alleviating ER stress and protecting chemoresistant breast cancer cells from apoptotic/necrotic cell death. These results highlight a possible strategy of targeting TM9SF4 to overcome breast cancer chemoresistance.
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18
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Gong T, Cui L, Wang H, Wang H, Han N. Knockdown of KLF5 suppresses hypoxia-induced resistance to cisplatin in NSCLC cells by regulating HIF-1α-dependent glycolysis through inactivation of the PI3K/Akt/mTOR pathway. J Transl Med 2018; 16:164. [PMID: 29898734 PMCID: PMC6000925 DOI: 10.1186/s12967-018-1543-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 06/07/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Hypoxia-mediated chemoresistance has been regarded as an important obstacle in the development of cancer treatment. Knockdown of krüppel-like factor 5 (KLF5) was reported to inhibit hypoxia-induced cell survival and promote cell apoptosis in non-small cell lung cancer (NSCLC) cells via direct regulation of hypoxia inducible factor-1α (HIF-1α) expression. However, the roles of KLF5 in the development of hypoxia-induced cisplatin (DDP) resistance and its underlying mechanism in NSCLC cells remain to be further elucidated. METHODS Western blot was performed to determine the protein levels of KLF5, P-glycoprotein (P-gp) and HIF-1α in treated NSCLC cells. Cell survival was examined by MTT assay. The effect of KLF5 knockdown on hypoxia-induced glycolysis was assessed by measuring glucose consumption and lactate production. The effect of KLF5 knockdown on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway was analyzed by western blot. RESULTS Hypoxia upregulated the expression of KLF5 in NSCLC cells. KLF5 knockdown suppressed hypoxia-induced DDP resistance in NSCLC cells, as demonstrated by the increased cytotoxic effects of DDP and reduced P-gp expression in NSCLC cells in hypoxia. Moreover, KLF5 knockdown inhibited hypoxia-induced HIF-1α expression and glycolysis, and KLF5 knockdown suppressed hypoxia-induced DDP resistance by inhibiting HIF-1α-dependent glycolysis in NSCLC cells. Furthermore, KLF5 knockdown suppressed hypoxia-induced activation of the PI3K/Akt/mTOR pathway in NSCLC cells and KLF5 overexpression promoted hypoxia-induced DDP resistance in NSCLC cells through activation of the PI3K/Akt/mTOR pathway. CONCLUSIONS KLF5 knockdown could suppress hypoxia-induced DDP resistance, and its mechanism may be due to the inhibition of HIF-1α-dependent glycolysis via inactivation of the PI3K/Akt/mTOR pathway.
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Affiliation(s)
- Tianxiao Gong
- Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jingba Road, Zhengzhou, 450014, People's Republic of China
| | - Liuqing Cui
- College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou, 450001, People's Republic of China.
| | - Haili Wang
- Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jingba Road, Zhengzhou, 450014, People's Republic of China
| | - Haoxun Wang
- Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jingba Road, Zhengzhou, 450014, People's Republic of China
| | - Na Han
- Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jingba Road, Zhengzhou, 450014, People's Republic of China
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19
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Rozic G, Paukov L, Jakubikova J, Ben-Shushan D, Duek A, Leiba A, Avigdor A, Nagler A, Leiba M. The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo. Oncotarget 2018; 7:62572-62584. [PMID: 27613836 PMCID: PMC5308747 DOI: 10.18632/oncotarget.11539] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 08/09/2016] [Indexed: 12/31/2022] Open
Abstract
Despite advances in treatment, multiple myeloma (MM) remains incurable. Here we propose the use of STK405759, a novel microtubule targeting agent (MTA) and member of the furan metotica family for MM therapy. STK405759 inhibited tubulin polymerization in a cell-free system and in myeloma cells. This molecule had potent cytotoxic activity against several MM cell lines and patient-derived MM cells. Moreover, STK405759 demonstrated cytotoxicity against drug-resistant myeloma cells that overexpressed the P-glycoprotein drug-efflux pump. STK405759 was not cytotoxic to peripheral blood mononuclear cells, including activated B and T lymphocytes. This compound caused mitotic arrest and apoptosis of myeloma cells characterized by cleavage of poly (ADP-ribose) polymerase-1 and caspase-8, as well as decreased protein expression of mcl-1. The combination of STK405759 with bortezomib, lenalidomide or dexamethasone had synergistic cytotoxic activity. In in vivo studies, STK405759-treated mice had significantly decreased MM tumor burden and prolonged survival compared to vehicle treated- mice. These results provide a rationale for further evaluation of STK405759 as monotherapy or part of combination therapy for treating patients with MM.
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Affiliation(s)
- Gabriela Rozic
- Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Lena Paukov
- Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Jana Jakubikova
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Dikla Ben-Shushan
- Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Adrian Duek
- Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Adi Leiba
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Medical Education, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA
| | - Abraham Avigdor
- Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Arnon Nagler
- Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Merav Leiba
- Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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20
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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.
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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
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21
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Bao J, Xu Y, Wang Q, Zhang J, Li Z, Li D, Li J. miR-101 alleviates chemoresistance of gastric cancer cells by targeting ANXA2. Biomed Pharmacother 2017; 92:1030-1037. [PMID: 28609840 DOI: 10.1016/j.biopha.2017.06.011] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 06/05/2017] [Accepted: 06/05/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Chemoresistance remains a main clinical obstacle in the treatment of gastric cancer (GC). microRNAs have been revealed to participate in the regulation of drug resistance in a variety of cancers. However, little is known about the function and detailed molecular mechanism of miR-101 in GC chemoresistance. METHODS The expressions of miR-101 and Annexin A2 (ANXA2) in GC tissues and cells were detected by qRT-PCR and western blot. The effects of miR-101 overexpression on P-glycoprotein (P-gp) at mRNA and protein levels, cell viability, and apoptosis in drug-resistant GC cells were examined by qRT-PCR, western blot, MTT and flow cytometry analysis, respectively. Luciferase reporter assay, RNA immunoprecipitation (RIP) and qRT-PCR were applied to confirm whether miR-101 could target ANXA2 and regulate its expression. Rescue experiment was performed to verify the mechanism by which miR-101 involved in chemoresistance. RESULTS miR-101 was downregulated in GC tissues and drug-resistant GC cells. A negative correlation between miR-101 and ANXA2 expression was observed in GC tissues. Forced expression of miR-101 significantly reduced P-gp expression at mRNA and protein levels in drug-resistant GC cells. Overexpression of miR-101 enhanced sensitivity to cisplatin (DDP) or vincristine (VCR) via viability inhibition and apoptosis promotion. ANXA2 was identified as a direct target of miR-101 and miR-101 negatively regulated ANXA2 expression. Moreover, ectopic expression of ANXA2 reversed the effect of miR-101 on P-gp expression, cell viability and apoptosis. CONCLUSION miR-101 alleviated chemoresistance of gastric cancer cells by targeting ANXA2. Therefore, targeting miR-101 may be a potential therapeutic approach for drug-resistant GC.
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Affiliation(s)
- Jie Bao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Yun Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Qunying Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Jinping Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Zhenjie Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Dongying Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Jiansheng Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
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Gil JP, Krishna S. pfmdr1 (Plasmodium falciparum multidrug drug resistance gene 1): a pivotal factor in malaria resistance to artemisinin combination therapies. Expert Rev Anti Infect Ther 2017; 15:527-543. [DOI: 10.1080/14787210.2017.1313703] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- J. Pedro Gil
- Physiology and Pharmacology Department, Karolinska Institutet, Stockholm, Sweden
| | - S. Krishna
- St George’s University Hospital, Institute for Infection and Immunity, London, United Kingdom
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Kudryavtsev VA, Khokhlova AV, Mosina VA, Selivanova EI, Kabakov AE. Induction of Hsp70 in tumor cells treated with inhibitors of the Hsp90 activity: A predictive marker and promising target for radiosensitization. PLoS One 2017; 12:e0173640. [PMID: 28291803 PMCID: PMC5349677 DOI: 10.1371/journal.pone.0173640] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 02/23/2017] [Indexed: 01/03/2023] Open
Abstract
We studied a role of the inducible heat shock protein 70 (Hsp70) in cellular response to radiosensitizing treatments with inhibitors of the heat shock protein 90 (Hsp90) chaperone activity. Cell lines derived from solid tumors of different origin were treated with the Hsp90 inhibitors (17AAG, geldanamycin, radicicol, NVP-AUY922) or/and γ-photon radiation. For comparison, human cells of the non-cancerous origin were subjected to the same treatments. We found that the Hsp90 inhibitors yielded considerable radiosensitization only when they cause early and pronounced Hsp70 induction; moreover, a magnitude of radiosensitization was positively correlated with the level of Hsp70 induction. The quantification of Hsp70 levels in Hsp90 inhibitor-treated normal and cancer cells enabled to predict which of them will be susceptible to any Hsp90-inhibiting radiosensitizer as well as what concentrations of the inhibitors ensure the preferential cytotoxicity in the irradiated tumors without aggravating radiation damage to adjacent normal tissues. Importantly, the Hsp70 induction in the Hsp90 inhibitor-treated cancer cells appears to be their protective response that alleviates the tumor-sensitizing effects of the Hsp90 inactivation. Combination of the Hsp70-inducing inhibitors of Hsp90 with known inhibitors of the Hsp induction such as quercetin, triptolide, KNK437, NZ28 prevented up-regulation of Hsp70 in the cancer cells thereby increasing their post-radiation apoptotic/necrotic death and decreasing their post-radiation viability/clonogenicity. Similarly, co-treatment with the two inhibitors conferred the enhanced radiosensitization of proliferating rather than quiescent human vascular endothelial cells which may be used for suppressing the tumor-stimulated angiogenesis. Thus, the easily immunodetectable Hsp70 induction can be a useful marker for predicting effects of Hsp90-inhibiting radiosensitizers on tumors and normal tissues exposed to ionizing radiation. Moreover, targeting the Hsp70 induction in Hsp90 inhibitor-treated cancer cells and tumor vasculature cells may beneficially enhance the radiosensitizing effect.
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Affiliation(s)
- Vladimir A. Kudryavtsev
- Department of Radiation Biochemistry, A. Tsyb Medical Radiological Research Center, Obninsk, Russia
| | - Anna V. Khokhlova
- Department of Radiation Biochemistry, A. Tsyb Medical Radiological Research Center, Obninsk, Russia
| | - Vera A. Mosina
- Department of Radiation Biochemistry, A. Tsyb Medical Radiological Research Center, Obninsk, Russia
| | - Elena I. Selivanova
- Department of Radiation Biochemistry, A. Tsyb Medical Radiological Research Center, Obninsk, Russia
| | - Alexander E. Kabakov
- Department of Radiation Biochemistry, A. Tsyb Medical Radiological Research Center, Obninsk, Russia
- * E-mail:
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24
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Teodori E, Dei S, Coronnello M, Floriddia E, Bartolucci G, Manetti D, Romanelli MN, Santo Domingo Porqueras D, Salerno M. N -alkanol- N -cyclohexanol amine aryl esters: Multidrug resistance (MDR) reversing agents with high potency and efficacy. Eur J Med Chem 2017; 127:586-598. [DOI: 10.1016/j.ejmech.2017.01.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 01/09/2017] [Accepted: 01/12/2017] [Indexed: 11/29/2022]
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25
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Tarapcsák S, Szalóki G, Telbisz Á, Gyöngy Z, Matúz K, Csősz É, Nagy P, Holb IJ, Rühl R, Nagy L, Szabó G, Goda K. Interactions of retinoids with the ABC transporters P-glycoprotein and Breast Cancer Resistance Protein. Sci Rep 2017; 7:41376. [PMID: 28145501 PMCID: PMC5286421 DOI: 10.1038/srep41376] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 12/20/2016] [Indexed: 01/16/2023] Open
Abstract
Retinoids – derivatives of vitamin A – are important cell permeant signaling molecules that regulate gene expression through activation of nuclear receptors. P-glycoprotein (Pgp) and ABCG2 are plasma membrane efflux transporters affecting the tissue distribution of numerous structurally unrelated lipophilic compounds. In the present work we aimed to study the interaction of the above ABC transporters with retinoid derivatives. We have found that 13-cis-retinoic acid, retinol and retinyl-acetate inhibited the Pgp and ABCG2 mediated substrate transport as well as the substrate stimulated ATPase activity of these transporters. Interestingly, 9-cis-retinoic acid and ATRA (all-trans retinoic acid), both are stereoisomers of 13-cis-retinoic acid, did not have any effect on the transporters’ activity. Our fluorescence anisotropy measurements revealed that 13-cis-retinoic acid, retinol and retinyl-acetate selectively increase the viscosity and packing density of the membrane. Thus, the mixed-type inhibition of both transporters by retinol and ABCG2 by 13-cis-retinoic acid may be the collective result of direct interactions of these retinoids with the substrate binding site(s) and of indirect interactions mediated by their membrane rigidifying effects.
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Affiliation(s)
- Szabolcs Tarapcsák
- Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, H-4002 Egyetem tér 1, P.O.B. 400, Hungary
| | - Gábor Szalóki
- Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, H-4002 Egyetem tér 1, P.O.B. 400, Hungary
| | - Ágnes Telbisz
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, H-1117 Magyar tudósok körútja 2, P.O.B. 286, Hungary
| | - Zsuzsanna Gyöngy
- Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, H-4002 Egyetem tér 1, P.O.B. 400, Hungary
| | - Krisztina Matúz
- Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4002 Egyetem tér 1, P.O.B. 400, Hungary
| | - Éva Csősz
- Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4002 Egyetem tér 1, P.O.B. 400, Hungary
| | - Péter Nagy
- Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, H-4002 Egyetem tér 1, P.O.B. 400, Hungary
| | - Imre J Holb
- Institute of Horticulture, University of Debrecen, Debrecen, H-4015 Böszörményi út 138, P.O.B. 400, Hungary.,Plant Protection Institute, Centre for Agricultural Research, Hungarian Academy of Sciences, Budapest, H-1525 Hermann Ottó út 15, P.O.B. 525, Hungary
| | - Ralph Rühl
- MTA-DE, Public Health Research Group of the Hungarian Academy of Sciences, Faculty of Public Health, University of Debrecen, Debrecen, H-4028 Kassai út 26, P.O.B. 400, Hungary
| | - László Nagy
- Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4002 Egyetem tér 1, P.O.B. 400, Hungary
| | - Gábor Szabó
- Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, H-4002 Egyetem tér 1, P.O.B. 400, Hungary
| | - Katalin Goda
- Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, H-4002 Egyetem tér 1, P.O.B. 400, Hungary
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Abstract
The development of drug resistance has largely limited the clinical outcome of anti-cancer treatment. Recent work has highlighted the involvement of non-coding RNAs, microRNAs (miRNAs), in cancer development. The present study aimed to investigate the role of miR-21 in the development of drug resistance to paclitaxel in gastric cancer cells. Our study found that the expression of miR-21 upregulated in the paclitaxel resistant cell line SGC7901/paclitaxel compared to its parental line SGC7901. Moreover, over-expression of miR-21 significantly decreased antiproliferative effects and apoptosis induced by paclitaxel, while knockdown of miR-21 dramatically increased antiproliferative effects and apoptosis induction by paclitaxel. Moreover, our results demonstrated that miR-21 may modulate the sensitivity to PTX, at least in part, by regulating the expression of P-glycoprotein.
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Lee J, An S, Choi YM, Lee J, Ahn KJ, Lee JH, Kim TJ, An IS, Bae S. Musashi-2 is a novel regulator of paclitaxel sensitivity in ovarian cancer cells. Int J Oncol 2016; 49:1945-1952. [PMID: 27600258 DOI: 10.3892/ijo.2016.3683] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 08/22/2016] [Indexed: 11/06/2022] Open
Abstract
As few prognostic markers and symptoms have been identified, ovarian cancer is typically diagnosed at an advanced stage, and a majority of patients will relapse and develop resistance to anticancer drugs such as paclitaxel. Musashi-2 (MSI2) is a regulator of gene translation and functions as an oncogenic protein and a marker of poor prognosis in various types of cancer. However, the biological and clinical significance of MSI2 in ovarian cancer remains unclear. Using a tissue microarray-based assay, we demonstrated that MSI2 was highly expressed in advanced, serous ovarian cancer tissues. In addition, MSI2-overexpressing ovarian cancer cells exhibited increased viability, proliferation and growth. We found that MSI2 was overexpressed in paclitaxel-resistant ovarian cancer SKOV3-TR cells but not in paclitaxel-sensitive cell lines. The loss of MSI2 expression in lentivirus-mediated stable MSI2 knockdown SKOV3-TR cells impaired paclitaxel resistance as determined using cell viability and apoptosis assays. In contrast, lentivirus-mediated MSI2 overexpression promoted the development of paclitaxel resistance in paclitaxel-sensitive ovarian cancer cells. The results of the present study are the first to demonstrate that MSI2 is a valuable marker of advanced, serous ovarian cancer and that MSI2 plays an important role in paclitaxel resistance.
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Affiliation(s)
- Jeongsuk Lee
- Research Institute for Molecular-Targeted Drugs, Department of Biological Engineering, Konkuk University, Seoul 05029, Republic of Korea
| | - Sungkwan An
- Research Institute for Molecular-Targeted Drugs, Department of Biological Engineering, Konkuk University, Seoul 05029, Republic of Korea
| | - Yeong Min Choi
- Research Institute for Molecular-Targeted Drugs, Department of Biological Engineering, Konkuk University, Seoul 05029, Republic of Korea
| | - Junwoo Lee
- Research Institute for Molecular-Targeted Drugs, Department of Biological Engineering, Konkuk University, Seoul 05029, Republic of Korea
| | - Kyu Joong Ahn
- Department of Dermatology, Konkuk University School of Medicine, Seoul 05030, Republic of Korea
| | - Jae Ho Lee
- Laboratory of Molecular Oncology, Cheil General Hospital and Women's Healthcare Center, Dankook University College of Medicine, Seoul 04619, Republic of Korea
| | - Tae Jin Kim
- Department of Obstetrics and Gynecology, Cheil General Hospital and Women's Healthcare Center, Dankook University College of Medicine, Seoul 04619, Republic of Korea
| | - In-Sook An
- Gene Cell Pharm Corporation, Cheongju-si, Chungcheongbuk-do 28160, Republic of Korea
| | - Seunghee Bae
- Research Institute for Molecular-Targeted Drugs, Department of Biological Engineering, Konkuk University, Seoul 05029, Republic of Korea
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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.
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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
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29
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Hansen SN, Ehlers NS, Zhu S, Thomsen MBH, Nielsen RL, Liu D, Wang G, Hou Y, Zhang X, Xu X, Bolund L, Yang H, Wang J, Moreira J, Ditzel HJ, Brünner N, Schrohl AS, Stenvang J, Gupta R. The stepwise evolution of the exome during acquisition of docetaxel resistance in breast cancer cells. BMC Genomics 2016; 17:442. [PMID: 27277198 PMCID: PMC4899892 DOI: 10.1186/s12864-016-2749-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 05/17/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Resistance to taxane-based therapy in breast cancer patients is a major clinical problem that may be addressed through insight of the genomic alterations leading to taxane resistance in breast cancer cells. In the current study we used whole exome sequencing to discover somatic genomic alterations, evolving across evolutionary stages during the acquisition of docetaxel resistance in breast cancer cell lines. RESULTS Two human breast cancer in vitro models (MCF-7 and MDA-MB-231) of the step-wise acquisition of docetaxel resistance were developed by exposing cells to 18 gradually increasing concentrations of docetaxel. Whole exome sequencing performed at five successive stages during this process was used to identify single point mutational events, insertions/deletions and copy number alterations associated with the acquisition of docetaxel resistance. Acquired coding variation undergoing positive selection and harboring characteristics likely to be functional were further prioritized using network-based approaches. A number of genomic changes were found to be undergoing evolutionary selection, some of which were likely to be functional. Of the five stages of progression toward resistance, most resistance relevant genomic variation appeared to arise midway towards fully resistant cells corresponding to passage 31 (5 nM docetaxel) for MDA-MB-231 and passage 16 (1.2 nM docetaxel) for MCF-7, and where the cells also exhibited a period of reduced growth rate or arrest, respectively. MCF-7 cell acquired several copy number gains on chromosome 7, including ABC transporter genes, including ABCB1 and ABCB4, as well as DMTF1, CLDN12, CROT, and SRI. For MDA-MB-231 numerous copy number losses on chromosome X involving more than 30 genes was observed. Of these genes, CASK, POLA1, PRDX4, MED14 and PIGA were highly prioritized by the applied network-based gene ranking approach. At higher docetaxel concentration MCF-7 subclones exhibited a copy number loss in E2F4, and the gene encoding this important transcription factor was down-regulated in MCF-7 resistant cells. CONCLUSIONS Our study of the evolution of acquired docetaxel resistance identified several genomic changes that might explain development of docetaxel resistance. Interestingly, the most relevant resistance-associated changes appeared to originate midway through the evolution towards fully resistant cell lines. Our data suggest that no single genomic event sufficiently predicts resistance to docetaxel, but require genomic alterations affecting multiple pathways that in concert establish the final resistance stage.
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Affiliation(s)
- Stine Ninel Hansen
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Section for Molecular Disease Biology, University of Copenhagen, Strandboulevarden 49, DK-2100, Copenhagen, Denmark
| | - Natasja Spring Ehlers
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet building 208, DK-2800, Lyngby, Denmark
| | - Shida Zhu
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China
| | - Mathilde Borg Houlberg Thomsen
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, DK-8200, Aarhus N, Denmark
| | - Rikke Linnemann Nielsen
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet building 208, DK-2800, Lyngby, Denmark
| | - Dongbing Liu
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China
| | - Guangbiao Wang
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China
| | - Yong Hou
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China
| | - Xiuqing Zhang
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China
| | - Xun Xu
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China
| | - Lars Bolund
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,Department of Biomedicine, Aarhus University, Bartholins Allé 6, DK-8000, Aarhus C, Denmark
| | - Huanming Yang
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China
| | - Jun Wang
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China.,Macau University of Science and Technology, Avenida Wai long, Taipa, Macau, 999078, China.,Department of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong.,Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 25, DK-5000, Odense, Denmark.,Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, DK-5000, Odense, Denmark
| | - Jose Moreira
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Section for Molecular Disease Biology, University of Copenhagen, Strandboulevarden 49, DK-2100, Copenhagen, Denmark
| | - Henrik J Ditzel
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200, Copenhagen, Denmark.,Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Nils Brünner
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Section for Molecular Disease Biology, University of Copenhagen, Strandboulevarden 49, DK-2100, Copenhagen, Denmark
| | - Anne-Sofie Schrohl
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark.,Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Section for Molecular Disease Biology, University of Copenhagen, Strandboulevarden 49, DK-2100, Copenhagen, Denmark
| | - Jan Stenvang
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark. .,Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Section for Molecular Disease Biology, University of Copenhagen, Strandboulevarden 49, DK-2100, Copenhagen, Denmark.
| | - Ramneek Gupta
- Sino Danish Breast Cancer Research Center, Copenhagen, Denmark. .,Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet building 208, DK-2800, Lyngby, Denmark.
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He DX, Gu F, Gao F, Hao JJ, Gong D, Gu XT, Mao AQ, Jin J, Fu L, Ma X. Genome-wide profiles of methylation, microRNAs, and gene expression in chemoresistant breast cancer. Sci Rep 2016; 6:24706. [PMID: 27094684 PMCID: PMC4837395 DOI: 10.1038/srep24706] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 03/30/2016] [Indexed: 12/17/2022] Open
Abstract
Cancer chemoresistance is regulated by complex genetic and epigenetic networks. In this study, the features of gene expression, methylation, and microRNA (miRNA) expression were investigated with high-throughput sequencing in human breast cancer MCF-7 cells resistant to adriamycin (MCF-7/ADM) and paclitaxel (MCF-7/PTX). We found that: ① both of the chemoresistant cell lines had similar, massive changes in gene expression, methylation, and miRNA expression versus chemosensitive controls. ② Pairwise integration of the data highlighted sets of genes that were regulated by either methylation or miRNAs, and sets of miRNAs whose expression was controlled by DNA methylation in chemoresistant cells. ③ By combining the three sets of high-throughput data, we obtained a list of genes whose expression was regulated by both methylation and miRNAs in chemoresistant cells; ④ Expression of these genes was then validated in clinical breast cancer samples to generate a 17-gene signature that showed good predictive and prognostic power in triple-negative breast cancer patients receiving anthracycline-taxane-based neoadjuvant chemotherapy. In conclusion, our results have generated a new workflow for the integrated analysis of the effects of miRNAs and methylation on gene expression during the development of chemoresistance.
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Affiliation(s)
- Dong-Xu He
- National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China
| | - Feng Gu
- Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, PR China
| | - Fei Gao
- Agricultural Genomes Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China
| | - Jun-jun Hao
- State Key Lab of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Desheng Gong
- Agricultural Genomes Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China
| | - Xiao-Ting Gu
- Department of Cellular and Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
| | - Ai-Qin Mao
- Department of Cellular and Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
| | - Jian Jin
- Department of Cellular and Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
| | - Li Fu
- Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, PR China
| | - Xin Ma
- Department of Cellular and Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
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Gutay-Tóth Z, Fenyvesi F, Bársony O, Szente L, Goda K, Szabó G, Bacsó Z. Cholesterol-dependent conformational changes of P-glycoprotein are detected by the 15D3 monoclonal antibody. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:188-95. [DOI: 10.1016/j.bbalip.2015.12.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/23/2015] [Accepted: 12/11/2015] [Indexed: 01/08/2023]
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Ding Y, Yu AQ, Wang XL, Guo XR, Yuan YH, Li DS. Forced expression of Nanog with mRNA synthesized in vitro to evaluate the malignancy of HeLa cells through acquiring cancer stem cell phenotypes. Oncol Rep 2016; 35:2643-50. [PMID: 26936116 DOI: 10.3892/or.2016.4639] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 10/05/2015] [Indexed: 11/06/2022] Open
Abstract
Nanog is a pluripotency-related factor. It was also found to play an important role in tumorigenesis. To date, the mechanisms underlying cervical tumorigenesis still need to be elucidated. In the present study, Nanog mRNA was synthesized in vitro and transfected into HeLa cells. After mRNA transfection, the forced expressed of Nanog in HeLa cells led to markedly increased invasion, migration, resistance to chemotherapeutic agents and dedifferentiation. In a subcutaneous xenograft assay, these cells had significantly increased tumorigenic capacity. Real-time PCR indicated that Nanog‑induced dedifferentiation was associated with increased expression of endogenous Oct4, Sox2 and FoxD3. In addition, the dedifferentiated HeLa cells acquired features associated with cancer stem cells (CSCs), such as multipotent differentiation capacity, and expression of CSC markers such as CD133. These data imply that Nanog is a positive regulator of cervical cancer dedifferentiation.
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Affiliation(s)
- Yan Ding
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Ai Qing Yu
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Xiao Li Wang
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Xing Rong Guo
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Ya Hong Yuan
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Dong Sheng Li
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
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Ye S, Zhang J, Shen J, Gao Y, Li Y, Choy E, Cote G, Harmon D, Mankin H, Gray NS, Hornicek FJ, Duan Z. NVP-TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P-glycoprotein (PGP1) function. Br J Pharmacol 2016; 173:613-26. [PMID: 26603906 PMCID: PMC4728419 DOI: 10.1111/bph.13395] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 09/23/2015] [Accepted: 11/19/2015] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND AND PURPOSE Increased expression of P-glycoprotein (PGP1) is one of the major causes of multidrug resistance (MDR) in cancer, including in osteosarcoma, which eventually leads to the failure of cancer chemotherapy. Thus, there is an urgent need to develop effective therapeutic strategies to override the expression and function of PGP1 to counter MDR in cancer patients. EXPERIMENTAL APPROACH In an effort to search for new chemical entities targeting PGP1-associated MDR in osteosarcoma, we screened a 500+ compound library of known kinase inhibitors with established kinase selectivity profiles. We aimed to discover potential drug synergistic effects among kinase inhibitors and general chemotherapeutics by combining inhibitors with chemotherapy drugs such as doxorubicin and paclitaxel. The human osteosarcoma MDR cell lines U2OSR2 and KHOSR2 were used for the initial screen and secondary mechanistic studies. KEY RESULTS After screening 500+ kinase inhibitors, we identified NVP-TAE684 as the most effective MDR reversing agent. NVP-TAE684 significantly reversed chemoresistance when used in combination with doxorubicin, paclitaxel, docetaxel, vincristine, ET-743 or mitoxantrone. NVP-TAE684 itself is not a PGP1 substrate competitive inhibitor, but it can increase the intracellular accumulation of PGP1 substrates in PGP1-overexpressing cell lines. NVP-TAE684 was found to inhibit the function of PGP1 by stimulating PGP1 ATPase activity, a phenomenon reported for other PGP1 inhibitors. CONCLUSIONS AND IMPLICATIONS The application of NVP-TAE684 to restore sensitivity of osteosarcoma MDR cells to the cytotoxic effects of chemotherapeutics will be useful for further study of PGP1-mediated MDR in human cancer and may ultimately benefit cancer patients.
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Affiliation(s)
- Shunan Ye
- Center for Sarcoma and Connective Tissue Oncology, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Jianming Zhang
- Cutaneous Biology Research Center, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Jacson Shen
- Center for Sarcoma and Connective Tissue Oncology, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Yan Gao
- Center for Sarcoma and Connective Tissue Oncology, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Ying Li
- Cutaneous Biology Research Center, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Edwin Choy
- Center for Sarcoma and Connective Tissue Oncology, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Gregory Cote
- Center for Sarcoma and Connective Tissue Oncology, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - David Harmon
- Center for Sarcoma and Connective Tissue Oncology, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Henry Mankin
- Center for Sarcoma and Connective Tissue Oncology, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | | | - Francis J Hornicek
- Center for Sarcoma and Connective Tissue Oncology, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Zhenfeng Duan
- Center for Sarcoma and Connective Tissue Oncology, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
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Liu S, Sun J, Cai B, Xi X, Yang L, Zhang Z, Feng Y, Sun Y. NANOG regulates epithelial-mesenchymal transition and chemoresistance through activation of the STAT3 pathway in epithelial ovarian cancer. Tumour Biol 2016; 37:9671-80. [PMID: 26801672 DOI: 10.1007/s13277-016-4848-x] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 01/13/2016] [Indexed: 01/06/2023] Open
Abstract
NANOG is a key transcription factor that is overexpressed and plays an important role in various cancers. Its overexpression is associated with highly tumorigenic, drug-resistant, and poor prognosis. However, the underlying mechanism of action of NANOG in ovarian cancer remains unclear. Epithelial-mesenchymal transition (EMT), which is a critical process in cancer invasion and metastasis, is also associated with drug resistance. We determined whether NANOG is associated with EMT and chemoresistance in epithelial ovarian cancer cells. NANOG expression was increased in epithelial ovarian cancer cells (HEY and SKOV3) compared with normal epithelial ovarian cells (Moody). Low expression of NANOG increased the expression of E-cadherin and decreased the expression of vimentin, β-catenin, and Snail. Furthermore, the cell migration and invasion abilities were decreased. The multidrug resistance genes MDR-1 and GST-π were also downregulated when NANOG was lowly expressed. The cells that were transfected with the si-NANOG plasmid were more sensitive to cisplatin compared with the cells that were transfected with empty vector. The data demonstrated that Stat3 was correlated with NANOG-mediated EMT and drug resistance. The silencing of Stat3 expression abrogated NANOG-mediated EMT changes and increased the sensitivity of the cells to chemotherapy. These results suggest that NANOG mediates EMT and drug resistance through activation of the Stat3 pathway in epithelial ovarian cancer.
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Affiliation(s)
- Suqing Liu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 201600
| | - Jing Sun
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 201600
| | - Bin Cai
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 201600
| | - Xiaowei Xi
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 201600
| | - Liu Yang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 201600
| | - Zhenbo Zhang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 201600
| | - Youji Feng
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 201600
| | - Yunyan Sun
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 201600.
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Extracellular vesicles in breast cancer drug resistance and their clinical application. Tumour Biol 2016; 37:2849-61. [PMID: 26797784 DOI: 10.1007/s13277-015-4683-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 12/16/2015] [Indexed: 02/06/2023] Open
Abstract
Drug resistance currently represents a daunting challenge in the treatment of breast cancer patients. With an increased understanding of the underlying mechanisms of drug resistance, the role of extracellular vesicles (EVs) in the development of chemo-insensitivity attracts extensive attention. EVs are membrane-limited, cell type-dependent vesicles that are secreted by normal or malignant cells. EVs comprise various types of contents, including genetic cargoes, proteins, and specific lipids. The characteristics of the contents determine their specific functions in not only physiological but also pathological conditions. It has been demonstrated that miRNAs and proteins in EVs are strongly correlated with breast cancer drug resistance. Additionally, they may exert an influence on de novo and acquired resistance bioprocesses. With the advances in extraction and detection technologies, EVs have also been employed to precisely diagnose and predict the outcome of therapy in breast cancer. On the other hand, they can also be exploited as efficient delivery system in future anticancer applications. In this paper, we summarized relative mechanisms concerning the relationship between EVs and breast cancer drug resistance, and then, we provide up-to-date research advances in the clinical application of EVs.
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36
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Story of Eribulin Mesylate: Development of the Longest Drug Synthesis. TOPICS IN HETEROCYCLIC CHEMISTRY 2016. [DOI: 10.1007/7081_2016_201] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Zheng H, Liu Z, Liu T, Cai Y, Wang Y, Lin S, Chen J, Wang J, Wang Z, Jiang B. Fas signaling promotes chemoresistance in gastrointestinal cancer by up-regulating P-glycoprotein. Oncotarget 2015; 5:10763-77. [PMID: 25333257 PMCID: PMC4279408 DOI: 10.18632/oncotarget.2498] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 09/16/2014] [Indexed: 12/28/2022] Open
Abstract
Fas signaling promotes metastasis of gastrointestinal (GI) cancer cells by inducing epithelial-mesenchymal transition (EMT), and EMT acquisition has been found to cause cancer chemoresistance. Here, we demonstrated that the response to chemotherapy of GI cancer patients with higher expression of FasL was significantly worse than patients with lower expression. Fas-induced activation of the ERK1/2-MAPK pathway decreased the sensitivity of GI cancer cells to chemotherapeutic agents and promoted the expression of P-glycoprotein (P-gp). FasL promoted chemoresistance of GI cancer cell via upregulation of P-gp by increasing β-catenin and decreasing miR-145. β-catenin promoted P-gp gene transcription by binding with P-gp promoter while miR-145 suppressed P-gp expression by interacting with the mRNA 3'UTR of P-gp. Immunostaining and qRT-PCR analysis of human GI cancer samples revealed a positive association among FasL, β-catenin, and P-gp, but a negative correlation between miR-145 and FasL or P-gp. Altogether, our results showed Fas signaling could promote chemoresistance in GI cancer through modulation of P-gp expression by β-catenin and miR-145. Our findings suggest that Fas signaling-based cancer therapies should be administered cautiously, as activation of this pathway may not only lead to apoptosis but also induce chemoresistance.
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Affiliation(s)
- Haoxuan Zheng
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhizhong Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Department of Gastroenterology, the Second People's Hospital of Zhuhai, Zhuhai 519020, China
| | - Tao Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yidong Cai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Yadong Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Shiyong Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Department of Endoscopy and Laser, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Jinmin Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jing Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhiqing Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Bo Jiang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Cui Y, Yang F, He L. Cytokine-induced killer cells induce apoptosis and inhibit the Akt/nuclear factor-κB signaling pathway in cisplatin-resistant human glioma U87MG cells. Mol Med Rep 2015; 12:7027-32. [PMID: 26299434 DOI: 10.3892/mmr.2015.4236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 07/22/2015] [Indexed: 11/06/2022] Open
Abstract
Despite advances in the development of treatment methods, glioma remains among the cancer types with a high rate of mortality. Therefore, significant efforts are made to develop novel strategies for the treatment of glioma. Ineffective, long-term cancer chemotherapy can lead to multidrug resistance (MDR), which is one of the most common reasons for the failure of chemotherapy. The present study investigated the effects of cytokine‑induced killer cells (CIK) on reversing MDR in cisplatin-resistant U87MG cells (U87MG/DDP). Mononuclear cells were isolated from the peripheral blood of healthy individuals and cultured in vitro in the presence of a combination of cytokines to generate CIK for the treatment of U87MG/DDP. An MTS assay, flow cytometric analysis of apoptosis, ELISA, western blotting and reverse transcription quantitative polymerase chain reaction were used to investigate the MDR-reversing effects of CIK as well as the underlying mechanisms. The results showed that cisplatin sensitivity and the apoptotic rate following cisplatin treatment were increased, P‑glycoprotein expression was decreased and the intracellular rhodamine‑123 content was increased in U87MG/DDP co‑cultured with CIK. In addition, the present study also identified increased mRNA and protein expression levels of MDR gene 1 (MDR1), MDR‑associated protein 1 (MRP1), B-cell lymphoma 2, Survivin and glutathione S-transferase‑π, while the phosphorylation of AKT and the transcriptional activity of nuclear factor‑κB in CIK co‑cultured U87MG/DDP was decreased. These results indicated that pre‑treatment with CIK reversed the MDR of U87MG/DDP, and that CIK‑induced apoptosis of U87MG/DDP was associated with the inhibition of Akt/NF‑κB. These findings suggested that treatment with CIK may be an effective method to enhance the sensitivity of patients with glioma to chemotherapy.
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Affiliation(s)
- Yunpeng Cui
- Department of Clinical Laboratory, Tianjin Huanhu Hospital, Tianjin 300060, P.R. China
| | - Feng Yang
- Department of Neurosurgery, The Sixth People's Hospital of Chongqing City, Chongqing 400060, P.R. China
| | - Lu He
- Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, P.R. China
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Kuroda K, Okumura K, Isogai H, Isogai E. The Human Cathelicidin Antimicrobial Peptide LL-37 and Mimics are Potential Anticancer Drugs. Front Oncol 2015; 5:144. [PMID: 26175965 PMCID: PMC4485164 DOI: 10.3389/fonc.2015.00144] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 06/15/2015] [Indexed: 01/08/2023] Open
Abstract
Antimicrobial peptides (AMPs) play a critical role in innate host defense against microbial pathogens in many organisms. The human cathelicidin, LL-37, has a net positive charge and is amphiphilic, and can eliminate pathogenic microbes directly via electrostatic attraction toward negatively charged bacterial membranes. A number of studies have shown that LL-37 participates in various host immune systems, such as inflammatory responses and tissue repair, in addition to its antibacterial properties. Moreover, recent evidence suggests that it is also involved in the regulation of cancer. Indeed, previous studies have suggested that human LL-37 is involved in carcinogenesis via multiple reporters, such as FPR2 (FPRL1), epidermal growth factor receptor, and ERBb2, although LL-37 and its fragments and analogs also show anticancer effects in various cancer cell lines. This discrepancy can be attributed to peptide-based factors, host membrane-based factors, and signal regulation. Here, we describe the association between AMPs and cancer with a focus on anticancer peptide functions and selectivity in an effort to understand potential therapeutic implications.
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Affiliation(s)
- Kengo Kuroda
- Laboratory of Animal Microbiology, Graduate School of Agricultural Science, Tohoku University , Sendai , Japan
| | - Kazuhiko Okumura
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Health Sciences University of Hokkaido , Hokkaido , Japan
| | - Hiroshi Isogai
- Animal Research Center, Sapporo Medical University , Sapporo , Japan
| | - Emiko Isogai
- Laboratory of Animal Microbiology, Graduate School of Agricultural Science, Tohoku University , Sendai , Japan
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40
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Ding Y, Yu AQ, Li CL, Fang J, Zeng Y, Li DS. TALEN-mediated Nanog disruption results in less invasiveness, more chemosensitivity and reversal of EMT in Hela cells. Oncotarget 2015; 5:8393-401. [PMID: 25245189 PMCID: PMC4226691 DOI: 10.18632/oncotarget.2298] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Emerging evidence suggests that Nanog is involved in cervical tumorigenesis. However, the regulating role of Nanog in tumorigenesis and chemosensitivity are still poorly understood. In this study, Nanog was disrupted by transcription activatorlike effector nucleases (TALEN) in Hela cells and its expression was significantly decreased in a single-cell derived sub-clone with biallelic mutations. The disruption of Nanog not only induced down regulation of some other core transcription factor genes for cell self-renewal, such as Oct4, Sox2 and FoxD3, but also led to the down regulation of some mesenchymal representative genes, vimentin and N-adherin, and up regulation of the epithelial gene, E-cadherin. In addition, the invasiveness and clonogenicity of the Hela cells were obviously affected, and surprisingly their sensitivities to anti-cancer drugs were also significantly increased in vitro. After Xenograft into nude mice, the growth volumes of the neoplasms from the Nanog disrupted Hela cells were significantly smaller compared with those from wild type ones. In conclusion, these results suggest that disruption of Nanog may reverse the status of epithelial-mesenchymal transition, which is critical in tumorigenesis, and alleviate chemoresistance, as well as their invasiveness, in cervical cancer cells.
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Affiliation(s)
- Yan Ding
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China. College of Life Science and Bioengineering, Beijing University of Industry, Beijing, China
| | - Ai Qing Yu
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Cheng Lin Li
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Juan Fang
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Yi Zeng
- College of Life Science and Bioengineering, Beijing University of Industry, Beijing, China
| | - Dong Sheng Li
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
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Wu LX, Wen CJ, Li Y, Zhang X, Shao YY, Yang Z, Zhou HH. Interindividual epigenetic variation in ABCB1 promoter and its relationship with ABCB1 expression and function in healthy Chinese subjects. Br J Clin Pharmacol 2015; 80:1109-21. [PMID: 25940551 DOI: 10.1111/bcp.12675] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Revised: 04/25/2015] [Accepted: 04/30/2015] [Indexed: 12/15/2022] Open
Abstract
AIM Interindividual epigenetic variation is likely to be an important mechanism contributing to the interindividual variability in the expression and function of ATP-binding cassette, sub-family B, member 1 (ABCB1). The aim of the present study was to explore the effect of interindividual epigenetic variability in the ABCB1 promoter on ABCB1 expression and function in healthy Chinese subjects. METHODS Using bisulfite sequencing polymerase chain reaction (PCR) and chromatin immunoprecipitation assays, the DNA methylation and histone acetylation status of the ABCB1 promoter in stool DNA and exfoliated colonic epithelial cells of 157 healthy Chinese male volunteers was analysed. ABCB1 mRNA levels in colonic epithelial cells were detected by real-time PCR. The digoxin pharmacokinetics in subjects with different epigenetic profiles was investigated after a single oral administration of digoxin (0.5 mg). RESULTS The methylation levels of ABCB1 promoter in stool DNA showed a significant interindividual variation, from 0.84% to 18.05%. A high methylation level of the ABCB1 promoter was closely related to the low levels of acetylated histone H3 and ABCB1 mRNA expression. In the high methylation group, the area under the concentration-time curves (AUC(0-4 h) and AUC(0-10 h) ) of digoxin was increased by 19% [95% confidence interval (CI) 10%, 31%; P = 0.024] and 13% (95% CI 8%, 26%; P = 0.026), respectively, and the peak concentration (Cmax ) of digoxin was increased by 30% (95% CI 12%, 41%; P = 0.021) compared with the low methylation group. CONCLUSIONS The epigenetic modifications of the ABCB1 promoter show high interindividual variability in healthy Chinese subjects, and are closely related to the interindividual variation in ABCB1 mRNA expression and digoxin 0-4 h plasma concentrations in vivo.
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Affiliation(s)
- Lan-Xiang Wu
- Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China
| | - Chun-Jie Wen
- Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China
| | - Ying Li
- Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China
| | - Xue Zhang
- Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China
| | - Ying-Ying Shao
- Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China
| | - Zhu Yang
- Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China
| | - Hong-Hao Zhou
- Institute of life sciences, Chongqing Medical University, Chongqing, P.R. China.,Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, P.R. China
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Chen JW, Wu QH, Rowley DC, Al-Kareef AMQ, Wang H. Anticancer agent-based marine natural products and related compounds. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2015; 17:199-216. [PMID: 25559315 DOI: 10.1080/10286020.2014.996140] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 12/03/2014] [Indexed: 06/04/2023]
Abstract
Marine natural products constitute a huge reservoir of anticancer agents. Consequently during the past decades, several marine anticancer compounds have been isolated, identified, and approved for anticancer treatment or are under trials. In this article the sources, structure, bioactivities, mode of actions, and analogs of some promising marine and derived anticancer compounds have been discussed.
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Affiliation(s)
- Jian-Wei Chen
- a College of Pharmaceutical Science, Zhejiang University of Technology , Hangzhou 310014 , P.R. China
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Ni X, Li L, Pan G. HDAC inhibitor-induced drug resistance involving ATP-binding cassette transporters (Review). Oncol Lett 2014; 9:515-521. [PMID: 25624882 PMCID: PMC4301560 DOI: 10.3892/ol.2014.2714] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 10/31/2014] [Indexed: 01/04/2023] Open
Abstract
Histone deacetylase (HDAC) inhibitors are becoming a novel and promising class of antineoplastic agents that have been used for cancer therapy in the clinic. Two HDAC inhibitors, vorinostat and romidepsin, have been approved by the Food and Drug Administration to treat T-cell lymphoma. Nevertheless, similar to common anticancer drugs, HDAC inhibitors have been found to induce multidrug resistance (MDR), which is an obstacle for the success of chemotherapy. The most common cause of MDR is considered to be the increased expression of adenosine triphosphate binding cassette (ABC) transporters. Numerous studies have identified that the upregulation of ABC transporters is often observed following treatment with HDAC inhibitors, particularly the increased expression of P-glycoprotein, which leads to drug efflux, reduces intracellular drug concentration and induces MDR. The present review summarizes the key ABC transporters involved in MDR following various HDAC inhibitor treatments in a range of cancer cell lines and also explored the potential mechanisms that result in MDR, including the effect of nuclear receptors, which are the upstream regulatory factors of ABC transporters.
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Affiliation(s)
- Xuan Ni
- Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China
| | - Li Li
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993-0002, USA
| | - Guoyu Pan
- Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China
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Wang T, Chen Z, Zhu Y, Pan Q, Liu Y, Qi X, Jin L, Jin J, Ma X, Hua D. Inhibition of transient receptor potential channel 5 reverses 5-Fluorouracil resistance in human colorectal cancer cells. J Biol Chem 2014; 290:448-56. [PMID: 25404731 DOI: 10.1074/jbc.m114.590364] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
5-Fluorouracil (5-Fu) is commonly used in the chemotherapy of colorectal cancer (CRC), but resistance to 5-Fu occurs in most cases, allowing cancer progression. Suppressing ABCB1 (ATP-binding cassette, subfamily B, member 1), which is a pump overproduced in cancer cells to export cytotoxic drugs, is an attractive strategy to overcome drug resistance. In the present study, transient receptor potential channel TrpC5 was found to be overproduced at the mRNA and protein levels together with ABCB1 in 5-Fu-resistant human CRC HCT-8 (HCT-8/5-Fu) and LoVo (LoVo/5-Fu) cells. More nuclear-stabilized β-catenin accumulation was found in HCT-8/5-Fu and LoVo/5-Fu cells than in HCT-8 and LoVo cells. Suppressing TrpC5 expression with TrpC5-specific siRNA inhibited the canonical Wnt/β-catenin signal pathway, reduced the induction of ABCB1, weakened the ABCB1 efflux pump, and caused a remarkable reversal of 5-Fu resistance in HCT-8/5-Fu and LoVo/5-Fu cells. On the contrary, enforcing TrpC5 expression resulted in an activated Wnt/β-catenin signal pathway and up-regulation of ABCB1. Taken together, we demonstrated an essential role of TrpC5 in ABCB1 induction and drug resistance in human CRC cells via promoting nuclear β-catenin accumulation.
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Affiliation(s)
- Teng Wang
- From the Departments of Medical Oncology and
| | - Zhen Chen
- the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Yifei Zhu
- the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Qiongxi Pan
- the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Yanjun Liu
- the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xiaowei Qi
- Pathology, Affiliated Hospital of Jiangnan University and Fourth People's Hospital of Wuxi, Wuxi, Jiangsu 214062, China and
| | - Linfang Jin
- Pathology, Affiliated Hospital of Jiangnan University and Fourth People's Hospital of Wuxi, Wuxi, Jiangsu 214062, China and
| | - Jian Jin
- the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xin Ma
- the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Dong Hua
- From the Departments of Medical Oncology and
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Dasari B, Jimmidi R, Arya P. Selected hybrid natural products as tubulin modulators. Eur J Med Chem 2014; 94:497-508. [PMID: 25455639 DOI: 10.1016/j.ejmech.2014.10.062] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 10/10/2014] [Accepted: 10/20/2014] [Indexed: 01/09/2023]
Abstract
Modulators of microtubule dynamics have received increasing attention because of their potential to stop cancer growth. Although it belongs to the category of complex protein-protein interactions (PPIs), which are generally considered difficult to modulate through small molecules, the use of microtubule is considered a well-validated target. There are a number of bioactive natural products and related compounds that are currently in use as drugs or in clinical trials as next generation anti-cancer agents. The present review article is focused on two such bioactive natural products, epothilone and halichondrin B, and covers some of the key papers published after 2005 that outline various synthetic approaches to obtain next generation structural analogs as well as the synthesis of hybrid compounds.
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Affiliation(s)
- Bhanudas Dasari
- Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, Telangana, India
| | - Ravikumar Jimmidi
- Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, Telangana, India
| | - Prabhat Arya
- Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, Telangana, India.
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18FDG, [18F]FLT, [18F]FAZA, and 11C-methionine are suitable tracers for the diagnosis and in vivo follow-up of the efficacy of chemotherapy by miniPET in both multidrug resistant and sensitive human gynecologic tumor xenografts. BIOMED RESEARCH INTERNATIONAL 2014; 2014:787365. [PMID: 25309926 PMCID: PMC4182689 DOI: 10.1155/2014/787365] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 08/14/2014] [Accepted: 08/28/2014] [Indexed: 01/19/2023]
Abstract
Expression of multidrug pumps including P-glycoprotein (MDR1, ABCB1) in the plasma membrane of tumor cells often results in decreased intracellular accumulation of anticancer drugs causing serious impediment to successful chemotherapy. It has been shown earlier that combined treatment with UIC2 anti-Pgp monoclonal antibody (mAb) and cyclosporine A (CSA) is an effective way of blocking Pgp function. In the present work we investigated the suitability of four PET tumor diagnostic radiotracers including 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)FDG), (11)C-methionine, 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT), and [(18)F]fluoroazomycin-arabinofuranoside ((18)FAZA) for in vivo follow-up of the efficacy of chemotherapy in both Pgp positive (Pgp(+)) and negative (Pgp(-)) human tumor xenograft pairs raised in CB-17 SCID mice. Pgp(+) and Pgp(-) A2780AD/A2780 human ovarian carcinoma and KB-V1/KB-3-1 human epidermoid adenocarcinoma tumor xenografts were used to study the effect of the treatment with an anticancer drug doxorubicin combined with UIC2 and CSA. The combined treatment resulted in a significant decrease of both the tumor size and the accumulation of the tumor diagnostic tracers in the Pgp(+) tumors. Our results demonstrate that (18)FDG, (18)F-FLT, (18)FAZA, and (11)C-methionine are suitable PET tracers for the diagnosis and in vivo follow-up of the efficacy of tumor chemotherapy in both Pgp(+) and Pgp(-) human tumor xenografts by miniPET.
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¹⁸FDG a PET tumor diagnostic tracer is not a substrate of the ABC transporter P-glycoprotein. Eur J Pharm Sci 2014; 64:1-8. [PMID: 25149126 DOI: 10.1016/j.ejps.2014.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 07/22/2014] [Accepted: 08/12/2014] [Indexed: 11/23/2022]
Abstract
2-[(18)F]fluoro-2-deoxy-d-glucose ((18)FDG) is a tumor diagnostic radiotracer of great importance in both diagnosing primary and metastatic tumors and in monitoring the efficacy of the treatment. P-glycoprotein (Pgp) is an active transporter that is often expressed in various malignancies either intrinsically or appears later upon disease progression or in response to chemotherapy. Several authors reported that the accumulation of (18)FDG in P-glycoprotein (Pgp) expressing cancer cells (Pgp(+)) and tumors is different from the accumulation of the tracer in Pgp nonexpressing (Pgp(-)) ones, therefore we investigated whether (18)FDG is a substrate or modulator of Pgp pump. Rhodamine 123 (R123) accumulation experiments and ATPase assay were used to detect whether (18)FDG is substrate for Pgp. The accumulation and efflux kinetics of (18)FDG were examined in two different human gynecologic (A2780/A2780AD and KB-3-1/KB-V1) and a mouse fibroblast (3T3 and 3T3MDR1) Pgp(+) and Pgp(-) cancer cell line pairs both in cell suspension and monolayer cultures. We found that (18)FDG and its derivatives did not affect either the R123 accumulation in Pgp(+) cells or the basal and the substrate stimulated ATPase activity of Pgp supporting that they are not substrates or modulators of the pump. Measuring the accumulation and efflux kinetics of (18)FDG in different Pgp(+) and Pgp(-) cell line pairs, we have found that the Pgp(+) cells exhibited significantly higher (p⩽0.01) (18)FDG accumulation and slightly faster (18)FDG efflux kinetics compared to their Pgp(-) counterparts. The above data support the idea that expression of Pgp may increase the energy demand of cells resulting in higher (18)FDG accumulation and faster efflux. We concluded that (18)FDG and its metabolites are not substrates of Pgp.
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Zhang FF, Zhu YF, Zhao QN, Yang DT, Dong YP, Jiang L, Xing WX, Li XY, Xing H, Shi M, Chen Y, Bruce IC, Jin J, Ma X. Microvesicles mediate transfer of P-glycoprotein to paclitaxel-sensitive A2780 human ovarian cancer cells, conferring paclitaxel-resistance. Eur J Pharmacol 2014; 738:83-90. [PMID: 24877693 DOI: 10.1016/j.ejphar.2014.05.026] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 04/28/2014] [Accepted: 05/11/2014] [Indexed: 01/26/2023]
Abstract
The overexpression of P-glycoprotein (P-gp) causes resistance to chemotherapy in human ovarian cancer. However, the underlying mechanism remains unclear. In the present study, we showed that, at membrane-bound protein level, P-gp was 'shared' between human ovarian cancer cells by the intercellular transfer of microvesicles (MVs). Paclitaxel-resistant human ovarian cancer cells (A2780/PTX) readily formed and released P-gp-containing MVs into the extracellular space compared with the wild-type parental line (A2780/WT). Shedding MVs bound to the chemosensitive A2780/WT cells in a time- and dose-dependent manner, transferring P-gp via the microenvironment. MV-mediated transfer of P-gp led to redistribution of the chemotherapeutic drug adriamycin in recipient cells (A2780/WT), which displayed 5- and 5-fold higher resistance to adriamycin and paclitaxel, respectively. Thus, these findings demonstrate a new mechanism of drug-resistance acquisition via MVs.
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Affiliation(s)
- Fang-fang Zhang
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Yi-fei Zhu
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Qian-nan Zhao
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Dan-tong Yang
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Ye-ping Dong
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Li Jiang
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Wei-xing Xing
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Xi-yuan Li
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Hui Xing
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Mei Shi
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Yun Chen
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Iain C Bruce
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China
| | - Jian Jin
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China.
| | - Xin Ma
- School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China.
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Zhou JJ, Deng XG, He XY, Zhou Y, Yu M, Gao WC, Zeng B, Zhou QB, Li ZH, Chen RF. Knockdown of NANOG enhances chemosensitivity of liver cancer cells to doxorubicin by reducing MDR1 expression. Int J Oncol 2014; 44:2034-40. [PMID: 24647772 DOI: 10.3892/ijo.2014.2347] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Accepted: 03/04/2014] [Indexed: 11/05/2022] Open
Abstract
Multidrug resistance (MDR) is one of the major reasons for the failure of liver cancer chemotherapy, and its suppression may increase the efficacy of chemotherapy. NANOG plays a key role in the regulation of embryonic stem cell self-renewal and pluripotency. Recent studies reported that NANOG was abnormally expressed in several types of tumors, indicating that NANOG is related to tumor development. However, the correlation between NANOG and liver cancer chemoresistance remains uncertain. In this study, RNA interfere technology was employed to knock down NANOG expression in HepG2 human liver cancer cells. We found that the knockdown of NANOG expression in NANOG siRNA-transfected HepG2 cells resulted in decreased colony formation rate and cell migration compared to control HepG2 cells. In addition, HepG2 cells were treated with doxorubicin to evaluate the chemosensitivity to doxorubicin. We found that the doxorubicin sensitivity of HepG2 cells was increased with downregulation of NANOG expression. The expression of MDR1 at both mRNA and protein levels was decreased in HepG2 cells when NANOG was knocked down. These findings suggest that the knockdown of NANOG in HepG2 human cells resulted in decreased MDR1 expression and increased doxorubicin sensitivity, and NANOG could be used as a novel potential therapeutic target to reverse multidrug resistance of liver cancer.
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Affiliation(s)
- Jia-Jia Zhou
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Xiao-Geng Deng
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Xiao-Yu He
- Laboratory of Biomechanics and Physiology, Guangdong Provincial Institute of Sports Science, Guangzhou, Guangdong, P.R. China
| | - Yu Zhou
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Min Yu
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Wen-Chao Gao
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Bing Zeng
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Quan-Bo Zhou
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Zhi-Hua Li
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Ru-Fu Chen
- Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
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MicroRNAs delivered by extracellular vesicles: an emerging resistance mechanism for breast cancer. Tumour Biol 2013; 35:2883-92. [DOI: 10.1007/s13277-013-1417-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 11/12/2013] [Indexed: 12/30/2022] Open
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