DOCSLIB.ORG

Binding Cassette Proteins (ABCB1 and ABCC1)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Binding Cassette Proteins (ABCB1 and ABCC1) South Dakota State University Open PRAIRIE: Open Public Research Access Institutional Repository and Information Exchange Electronic Theses and Dissertations 2021 Characterization of Cucurbitacin-Inspired Estrone Analogues as Novel Inhibitors of Human ATP- Binding Cassette Proteins (ABCB1 and ABCC1) Jennifer Kyeremateng South Dakota State University Follow this and additional works at: https://openprairie.sdstate.edu/etd Part of the Biochemistry Commons, Medical Biochemistry Commons, and the Oncology Commons Recommended Citation Kyeremateng, Jennifer, "Characterization of Cucurbitacin-Inspired Estrone Analogues as Novel Inhibitors of Human ATP- Binding Cassette Proteins (ABCB1 and ABCC1)" (2021). Electronic Theses and Dissertations. 5212. https://openprairie.sdstate.edu/etd/5212 This Dissertation - Open Access is brought to you for free and open access by Open PRAIRIE: Open Public Research Access Institutional Repository and Information Exchange. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Open PRAIRIE: Open Public Research Access Institutional Repository and Information Exchange. For more information, please contact [email protected]. CHARACTERIZATION OF CUCURBITACIN -INSPIRED ESTRONE ANALOGUES AS NOVEL INHIBITORS OF HUMAN ATP-BINDING CASSETTE PROTEINS (ABCB1 AND ABCC1) BY JENNIFER KYEREMATENG A dissertation submitted in partial fulfillment of the requirements for the Doctor of Philosophy Major in Biochemistry South Dakota State University 2021 ii DISSERTATION ACCEPTANCE PAGE Jennifer Kyeremateng This dissertation is approved as a creditable and independent investigation by a candidate for the Doctor of Philosophy degree and is acceptable for meeting the dissertation requirements for this degree. Acceptance of this does not imply that the conclusions reached by the candidate are necessarily the conclusions of the major department. Surtaj Iram Advisor Date Douglas Raynie Department Head Date Nicole Lounsbery, PhD Director, Graduate School Date iii This dissertation is dedicated to the Almighty God for establishing my existence and giving me the strength to achieve this feat in spite of my weakness. I am indebted to Your unconditional love in my life. And to the loving memory of my dearest father, Edmond Kyeremateng, who taught me that I can always achieve my dreams with determination, hard work, perseverance and patience. I am the individual I find myself today because of your constant reassurance. I wish you were here and I definitely know you will be proud of this achievement. iv ACKNOWLEDGEMENTS I would like to express my sincere gratitude to my academic advisor, Dr. Surtaj Iram for his guidance, mentorship and kind words of encouragement that pushed me farther beyond the limit I thought I could go. I am indebted to my advisory committee members, Prof. Fathi Halaweish, Dr. Rachel Willand Charnley, Prof. Alireza Salehnia and Dr. Severine Van Slambrouck (former committee member) for their periodic assessment of my research, timely support, guidance and being instrumental in helping this dissertation into completion. I am especially thankful to the Halaweish Lab group (Prof. Fathi Halaweish, Dr. Mater Mahnashi) for providing the compounds that enabled me to execute this study. I am also thankful to my lab colleagues for their constant support and assistance during my research work. I am grateful to the Department of Chemistry and Biochemistry and South Dakota State University for the unwavering financial support throughout my graduate studies. A huge gratitude goes to my fiancé, Dr. Aubrey Kusi-Appiah for his love, understanding and support and for not allowing me to give up when the going was tough. I am extremely grateful to my family for their love, prayers and sacrifices they have made in my life. To Aunt Doris and my awesome siblings, Christabel, Gloria, Kojo, Nana Boakye and Junior, thank you for understanding and tolerating my silence the past five years. Finally, I will like to thank my friends, my church family, Holy Life Tabernacle and the Brookings community for creating an amazing positive environment during my studies. v CONTENTS ABBREVIATIONS ......................................................................................................... viii LIST OF FIGURES .............................................................................................................x LIST OF TABLES ............................................................................................................ xii ABSTRACT ..................................................................................................................... xiii Chapter 1 ..............................................................................................................................1 Introduction and Background ...........................................................................................1 1.1 Cell Transport and Membrane Transport Proteins......................................................1 1.2 The ABC Transporter Family ....................................................................................3 1.3 Human ABC Transporter Genes and Associated Diseases ........................................5 1.3 Structure, Organization and Mechanistic function of ABC Transporters ..................9 1.5 Human ABC Transporters and Multidrug Resistance in Cancer .............................14 1.6 Permeability Glycoprotein (P-gp/ABCB1) ..............................................................16 1.7 Multidrug Resistance Protein 1 (MRP1/ABCC1) ....................................................19 1.8 Current strategies for P-gp and MRP1 inhibition ....................................................22 1.8.1 First generation P-gp inhibitors .........................................................................23 1.8.2 Second generation P-gp inhibitors .....................................................................24 1.8.3 Third generation P-gp inhibitors ........................................................................25 1.8.4 MRP1 Inhibitors ................................................................................................26 1.9 Natural Products as potential source of drug strategies against multidrug resistance in cancer .........................................................................................................................28 1.9.1 Cucurbitacins – origin and structure ..................................................................30 1.9.2 Cucurbitacins Antitumor Activities ...................................................................32 1.9.3 Cucurbitacin-inspired estrone analogs (CIEA)..................................................34 1.10 Biochemical Approaches for Studying ABC Transporter Modulators ..................35 1.10.1 High Content Fluorescence-based Screening ..................................................37 1.10.2 Flow cytometry-based Accumulation or Efflux Assays ..................................38 1.10.3 In Silico Molecular Docking Studies ...............................................................40 1.10.4 Fluorescence Spectroscopy – FRET ................................................................40 1.11 Research Strategy and Significance .......................................................................42 References ......................................................................................................................44 Chapter 2 ............................................................................................................................55 Abstract ..........................................................................................................................55 vi 2.1 Introduction ..............................................................................................................57 2.2 Materials and Methods .............................................................................................63 2.2.1 Chemicals ..........................................................................................................63 2.2.2 Cell lines and cell culture ..................................................................................63 2.2.3 High content fluorescence-based transporter activity assay for screening of CIEA library ...............................................................................................................64 2.2.4 Calcein-AM accumulation assay .......................................................................65 2.2.5 Doxorubicin accumulation assay .......................................................................66 2.2.6 Drug resistance reversal studies ........................................................................66 2.2.7 Western blot analysis .........................................................................................67 2.2.8 In silico molecular docking studies ...................................................................68 2.2.9 Fluorescence spectroscopic analysis .................................................................68 2.2.10 High content fluorescence inhibition screening data analysis .........................70 2.2.11 Statistical analysis............................................................................................71 2.3 Results ......................................................................................................................71 2.3.1 CIEA compound library screening for P-gp
Load more

Recommended publications
  • WO 2017/048702 Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date W O 2017/048702 A l 2 3 March 2017 (23.03.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 487/04 (2006.01) A61P 35/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/519 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US20 16/05 1490 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 13 September 2016 (13.09.201 6) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (25) Filing Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (26) Publication Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/218,493 14 September 2015 (14.09.2015) US (84) Designated States (unless otherwise indicated, for every 62/218,486 14 September 2015 (14.09.2015) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: INFINITY PHARMACEUTICALS, INC.
    [Show full text]
  • Natural Products As Alternative Choices for P-Glycoprotein (P-Gp) Inhibition
    Review Natural Products as Alternative Choices for P-Glycoprotein (P-gp) Inhibition Saikat Dewanjee 1,*, Tarun K. Dua 1, Niloy Bhattacharjee 1, Anup Das 2, Moumita Gangopadhyay 3, Ritu Khanra 1, Swarnalata Joardar 1, Muhammad Riaz 4, Vincenzo De Feo 5,* and Muhammad Zia-Ul-Haq 6,* 1 Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Raja S C Mullick Road, Kolkata 700032, India; [email protected] (T.K.D.); [email protected] (N.B.); [email protected] (R.K.); [email protected] (S.J.) 2 Department of Pharmaceutical Technology, ADAMAS University, Barasat, Kolkata 700126, India; [email protected] 3 Department of Bioechnology, ADAMAS University, Barasat, Kolkata 700126, India; [email protected] 4 Department of Pharmacy, Shaheed Benazir Bhutto University, Sheringal 18050, Pakistan; [email protected] 5 Department of Pharmacy, Salerno University, Fisciano 84084, Salerno, Italy 6 Environment Science Department, Lahore College for Women University, Jail Road, Lahore 54600, Pakistan * Correspondence: [email protected] (S.D.); [email protected] (V.D.F.); [email protected] (M.Z.-U.-H.) Academic Editor: Maria Emília de Sousa Received: 11 April 2017; Accepted: 15 May 2017; Published: 25 May 2017 Abstract: Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for numerous chemotherapeutic agents. Multiple key regulators are alleged to be responsible for MDR and making the treatment regimens ineffective. In this review, we discuss MDR in relation to P-glycoprotein (P-gp) and its down-regulation by natural bioactive molecules. P-gp, a unique ATP-dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc.
    [Show full text]
  • MINI-REVIEW Cancer Multidrug Resistance (MDR): a Major
    Cancer Multidrug Resistance: A Major Impediment to Effective Chemotherapy MINI-REVIEW Cancer Multidrug Resistance (MDR): A Major Impediment to Effective Chemotherapy Mohd Fahad Ullah Abstract Multidrug resistance (MDR) continues to be a major challenge to effective chemotherapeutic interventions against cancer. Various types of cancers have been observed to exhibit this phenomenon, a strategy that involves cellular and non cellular mechanisms employed by cancer cells to survive the cytotoxic actions of various structurally and functionally unrelated drugs. The present article is a brief review of the fundamental mechanisms underlying the phenomenon of MDR in cancer cells and some novel approaches addressed at its inhibition, circumvention or reversal. The emergence of natural products as potential anti-MDR molecules is of particular significance. Since many of these are essential components of the human diet, they are expected to possess fewer side effects and may possibly represent a new generation of MDR modulators. Key Words: Multidrug resistance - chemotherapy - mechanisms - natural modulators Asian Pacific J Cancer Prev, 9, 1-6 Introduction specificity in terms of origin, vasculature and tissue function. Tumors located in parts of the body where the The resistance of human tumor to multiple drug is not accessible or tumors with compromised chemotherapeutic drugs has been recognized as a major vasculature often show resistance to chemotherapy. The reason for the failure of cancer therapy (Gottesman and former specificity is linked
    [Show full text]
  • ABCD3 (F-1): Sc-514728
    SANTA CRUZ BIOTECHNOLOGY, INC. ABCD3 (F-1): sc-514728 BACKGROUND APPLICATIONS The peroxisomal membrane contains several ATP-binding cassette (ABC) ABCD3 (F-1) is recommended for detection of ABCD3 of human origin by transporters, ABCD1-4 that are known to be present in the human peroxisome Western Blotting (starting dilution 1:100, dilution range 1:100-1:1000), membrane. All four proteins are ABC half-transporters, which dimerize to form immunoprecipitation [1-2 µg per 100-500 µg of total protein (1 ml of cell an active transporter. A mutation in the ABCD1 gene causes X-linked adreno- lysate)], immunofluorescence (starting dilution 1:50, dilution range 1:50- leukodystrophy (X-ALD), a peroxisomal disorder which affects lipid storage. 1:500) and solid phase ELISA (starting dilution 1:30, dilution range 1:30- ABCD2 in mouse is expressed at high levels in the brain and adrenal organs, 1:3000). which are adversely affected in X-ALD. The peroxisomal membrane comprises Suitable for use as control antibody for ABCD3 siRNA (h): sc-41147, ABCD3 two quantitatively major proteins, PMP22 and ABCD3. ABCD3 is associated shRNA Plasmid (h): sc-41147-SH and ABCD3 shRNA (h) Lentiviral Particles: with irregularly shaped vesicles which may be defective peroxisomes or per- sc-41147-V. oxisome precursors. ABCD1 localizes to peroxisomes. ABCB7 is a half-trans- porter involved in the transport of heme from the mitochondria to the cytosol. Molecular Weight of ABCD3: 75 kDa. Positive Controls: HeLa whole cell lysate: sc-2200, SH-SY5Y cell lysate: REFERENCES sc-3812 or Caco-2 cell lysate: sc-2262.
    [Show full text]
  • PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1
    cancers Article PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1 Alice Matheux 1,2,†, Matthieu Gassiot 1,†,‡ , Gaëlle Fromont 3 , Fanny Leenhardt 1,4 , Abdelhay Boulahtouf 1 , Eric Fabbrizio 1 , Candice Marchive 1, Aurélie Garcin 1 , Hanane Agherbi 1, Eve Combès 1, Alexandre Evrard 1,2,4 , Nadine Houédé 1,5 , Patrick Balaguer 1 ,Céline Gongora 1 , Litaty C. Mbatchi 1,2,4 and Philippe Pourquier 1,* 1 IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France; [email protected] (A.M.); [email protected] (M.G.); [email protected] (F.L.); [email protected] (A.B.); [email protected] (E.F.); [email protected] (C.M.); [email protected] (A.G.); [email protected] (H.A.); [email protected] (E.C.); [email protected] (A.E.); [email protected] (N.H.); [email protected] (P.B.); [email protected] (C.G.); [email protected] (L.C.M.) 2 Laboratoire de Biochimie et Biologie Moléculaire, CHU Carémeau, F-30029 Nîmes, France 3 Département de Pathologie, CHU de Tours, Université François Rabelais, Inserm UMR 1069, F-37044 Tours, France; [email protected] 4 Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, Citation: Matheux, A.; Gassiot, M.; F-34090 Montpellier, France 5 Département d’Oncologie Médicale, Institut de Cancérologie du Gard—CHU Carémeau, Fromont, G.; Leenhardt, F.; Boulahtouf, F-30029 Nîmes, France A.; Fabbrizio, E.; Marchive, C.; Garcin, * Correspondence: [email protected]; Tel.: +33-4-66-68-32-31 A.; Agherbi, H.; Combès, E.; et al.
    [Show full text]
  • Transcriptional and Post-Transcriptional Regulation of ATP-Binding Cassette Transporter Expression
    Transcriptional and Post-transcriptional Regulation of ATP-binding Cassette Transporter Expression by Aparna Chhibber DISSERTATION Submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmaceutical Sciences and Pbarmacogenomies in the Copyright 2014 by Aparna Chhibber ii Acknowledgements First and foremost, I would like to thank my advisor, Dr. Deanna Kroetz. More than just a research advisor, Deanna has clearly made it a priority to guide her students to become better scientists, and I am grateful for the countless hours she has spent editing papers, developing presentations, discussing research, and so much more. I would not have made it this far without her support and guidance. My thesis committee has provided valuable advice through the years. Dr. Nadav Ahituv in particular has been a source of support from my first year in the graduate program as my academic advisor, qualifying exam committee chair, and finally thesis committee member. Dr. Kathy Giacomini graciously stepped in as a member of my thesis committee in my 3rd year, and Dr. Steven Brenner provided valuable input as thesis committee member in my 2nd year. My labmates over the past five years have been incredible colleagues and friends. Dr. Svetlana Markova first welcomed me into the lab and taught me numerous laboratory techniques, and has always been willing to act as a sounding board. Michael Martin has been my partner-in-crime in the lab from the beginning, and has made my days in lab fly by. Dr. Yingmei Lui has made the lab run smoothly, and has always been willing to jump in to help me at a moment’s notice.
    [Show full text]
  • ABC Transporter Subfamily D: Distinct Differences in Behavior Between ABCD1–3 and ABCD4 in Subcellular Localization, Function, and Human Disease
    Hindawi Publishing Corporation BioMed Research International Volume 2016, Article ID 6786245, 11 pages http://dx.doi.org/10.1155/2016/6786245 Review Article ABC Transporter Subfamily D: Distinct Differences in Behavior between ABCD1–3 and ABCD4 in Subcellular Localization, Function, and Human Disease Kosuke Kawaguchi and Masashi Morita Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan Correspondence should be addressed to Kosuke Kawaguchi; [email protected] Received 24 June 2016; Accepted 29 August 2016 Academic Editor: Hiroshi Nakagawa Copyright © 2016 K. Kawaguchi and M. Morita. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ATP-binding cassette (ABC) transporters are one of the largest families of membrane-bound proteins and transport a wide variety of substrates across both extra- and intracellular membranes. They play a critical role in maintaining cellular homeostasis. To date, four ABC transporters belonging to subfamily D have been identified. ABCD1–3 and ABCD4 are localized to peroxisomes and lysosomes, respectively. ABCD1 and ABCD2 are involved in the transport of long and very long chain fatty acids (VLCFA) or their CoA-derivatives into peroxisomes with different substrate specificities, while ABCD3 is involved in the transport of branched chain acyl-CoA into peroxisomes. On the other hand, ABCD4 is deduced to take part in the transport of vitamin B12 from lysosomes into the cytosol. It is well known that the dysfunction of ABCD1 results in X-linked adrenoleukodystrophy, a severe neurodegenerative disease.
    [Show full text]
  • ABC Transporter Regulation by Protein Phosphorylation in Plant and Mammalian Systems
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE Published in "Biochemical Society Transactions 44(2): 663–673, 2016" provided by RERO DOC Digital Library which should be cited to refer to this work. Correction: Learning from each other: ABC transporter regulation by protein phosphorylation in plant and mammalian systems Bibek Aryal*, Christophe Laurent* and Markus Geisler*1 *Department of Biology – Plant Biology, University of Fribourg, Rue Albert Gockel 3, PER04, CH-1700 Fribourg, Switzerland An incorrect version of the article was published in volume Importance of mammalian ABC 43 (issue 5) 966-974 (doi: 10.1042/BST20150128); the correct transporters version of the complete article is presented here. ATP-binding cassette (ABC) transporters are integral membrane proteins ubiquitously present in all phyla [1]. They use the energy of nucleoside triphosphate (mainly ATP) Abstract hydrolysis to pump their substrates across the membrane The ABC (ATP-binding cassette) transporter family in [1]. The list of described substrates is long and diverse and higher plants is highly expanded compared with those includes metabolic products, sugars, metal ions, hormones, of mammalians. Moreover, some members of the plant sterols, lipids and therapeutical drugs [1]. The ABC transport ABCB subfamily display very high substrate specificity nano-machinery encompasses two transmembrane domains compared with their mammalian counterparts that are often (TMDs) and two cytosolic nucleotide-binding domains associated with multidrug resistance (MDR) phenomena. In (NBDs). ATP hydrolysis results in a conformational change this review we highlight prominent functions of plant and of the NBDs, this in-turn brings the substrate across the mammalian ABC transporters and summarize our knowledge membrane in a unidirectional fashion [2].
    [Show full text]
  • Pathways of Chemotherapy Resistance in Castration-Resistant Prostate Cancer
    Endocrine-Related Cancer (2011) 18 R103–R123 REVIEW Pathways of chemotherapy resistance in castration-resistant prostate cancer Kate L Mahon1,2,3, Susan M Henshall3, Robert L Sutherland 3 and Lisa G Horvath1,2,3 1Department of Medical Oncology, Sydney Cancer Centre, Missenden Road, Camperdown, New South Wales 2050, Australia 2University of Sydney, City Road, Camperdown, New South Wales 2006, Australia 3Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia (Correspondence should be addressed to K L Mahon; Email: [email protected]) Abstract Chemotherapy remains the major treatment option for castration-resistant prostate cancer (CRPC) and limited cytotoxic options are available. Inherent chemotherapy resistance occurs in half of all patients and inevitably develops even in those who initially respond. Docetaxel has been the mainstay of therapy for 6 years, providing a small survival benefit at the cost of significant toxicity. Cabazitaxel is a promising second-line agent; however, it is no less toxic, whereas mitoxantrone provides only symptomatic benefit. Multiple cellular pathways involving apoptosis, inflammation, angiogenesis, signalling intermediaries, drug efflux pumps and tubulin are implicated in the development of chemoresistance. A thorough understanding of these pathways is needed to identify biomarkers that predict chemotherapy resistance with the aim to avoid unwarranted toxicities in patients who will not benefit from treatment. Until recently, the search for predictive biomarkers has been disappointing; however, the recent discovery of macrophage inhibitory cytokine 1 as a marker of chemoresistance may herald a new era of biomarker discovery in CRPC. Understanding the interface between this complex array of chemoresistance pathways rather than their study in isolation will be required to effectively predict response and target the late stages of advanced disease.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Identification of Novel Snps of ABCD1, ABCD2, ABCD3
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central Neurogenetics (2011) 12:41–50 DOI 10.1007/s10048-010-0253-6 ORIGINAL ARTICLE Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes Takashi Matsukawa & Muriel Asheuer & Yuji Takahashi & Jun Goto & Yasuyuki Suzuki & Nobuyuki Shimozawa & Hiroki Takano & Osamu Onodera & Masatoyo Nishizawa & Patrick Aubourg & Shoji Tsuji Received: 15 May 2010 /Accepted: 9 July 2010 /Published online: 27 July 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Adrenoleukodystrophy (ALD) is an X-linked dis- French ALD cohort with extreme phenotypes. All the order affecting primarily the white matter of the central mutations of ABCD1 were identified, and there was no nervous system occasionally accompanied by adrenal insuffi- correlation between the genotypes and phenotypes of ALD. ciency. Despite the discovery of the causative gene, ABCD1, SNPs identified by the comprehensive resequencing of no clear genotype–phenotype correlations have been estab- ABCD2, ABCD3,andABCD4 were used for association lished. Association studies based on single nucleotide poly- studies. There were no significant associations between these morphisms (SNPs) identified by comprehensive resequencing SNPs and ALD phenotypes, except for the five SNPs of of genes related to ABCD1 may reveal genes modifying ALD ABCD4, which are in complete disequilibrium in the phenotypes. We analyzed 40 Japanese patients with ALD. Japanese population. These five SNPs were significantly less ABCD1 and ABCD2 were analyzed using a newly developed frequently represented in patients with adrenomyeloneurop- microarray-based resequencing system.
    [Show full text]
  • Tumour Stem Cells and Drug Resistance
    REVIEWS TUMOUR STEM CELLS AND DRUG RESISTANCE Michael Dean*, Tito Fojo‡ and Susan Bates ‡ Abstract | The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters have been shown to protect cancer stem cells from chemotherapeutic agents. Gaining a better insight into the mechanisms of stem-cell resistance to chemotherapy might therefore lead to new therapeutic targets and better anticancer strategies. The discovery of cancer stem cells in solid tumours has demonstrated that most mammary cells have a limited changed our view of carcinogenesis and chemotherapy. capacity for self-renewal, clonal populations that can One of the unique features of the bone-marrow stem recapitulate the entire functional repertoire of the cells that are required for normal haematopoiesis is their gland have been identified5.In an elegant study, human capacity for self-renewal. In the haematopoietic system, mammary epithelial cells derived from reduction there are three different populations of multipotent mammoplasties were used to generate non-adherent progenitors — stem cells with a capacity for long-term spheroids (designated mammospheres) in cell culture renewal, stem cells with a capacity for short-term and demonstrate the presence of the three mammary renewal, and multipotent progenitors that cannot renew cell lineages. More importantly, the cells in the mam- but differentiate into the varied lineages in the bone mar- mospheres were clonally derived, providing evidence row1–3.The multipotent progenitors and their derived for a single pluripotent stem cell4.These same lineages undergo rapid cell division, allowing them to approaches are being used to isolate and characterize populate the marrow.
    [Show full text]