MicroRNAs in Diseases and Disorders Emerging Therapeutic Targets 1 0 0 P F 1- 2 4 6 1 0 8 8 7 1 8 7 9 9/ 3 0 1 0. 1 oi: d g | or c. s s.r b u p s:// p htt n o 9 1 0 2 y a M 7 0 on d e h s bli u P View Online Drug Discovery Series Editor-­in-c­hief David Thurston, King's­College,­UK 1 0 Series­editors: 0 P F David Fox, Vulpine­Science­and­Learning,­UK 1- 42 Ana Martinez, Centro­de­Investigaciones­Biologicas-­CSIC,­Spain 6 01 David Rotella, Montclair­State­University,­USA 8 78 Hong Shen, Roche­Innovation­Center­Shanghai,­China 1 8 7 9 9/ Editorial­advisor: 3 0 1 Ian Storer, AstraZeneca,­UK 0. 1 oi: d Titles­in­the­Series: g | or 1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups sc. 2: Emerging Drugs and Targets for Alzheimer's Disease; Volume 1 s.r b 3: Emerging Drugs and Targets for Alzheimer's Disease; Volume 2 u p s:// 4: Accounts in Drug Discovery http 5: New Frontiers in Chemical Biology n 6: Animal Models for Neurodegenerative Disease o 19 7: Neurodegeneration 0 y 2 8: G Protein- coupled Receptors a M 9: Pharmaceutical Process Development 7 0 10: Extracellular and Intracellular Signaling d on 11: New Synthetic Technologies in Medicinal Chemistry e h 12: New Horizons in Predictive Toxicology s bli 13: Drug Design Strategies: Quantitative Approaches u P 14: Neglected Diseases and Drug Discovery 15: Biomedical Imaging 16: Pharmaceutical Salts and Cocrystals 17: Polyamine Drug Discovery 18: Proteinases as Drug Targets 19: Kinase Drug Discovery 20: Drug Design Strategies: Computational Techniques and Applications 21: Designing Multi- target Drugs 22: Nanostructured Biomaterials for Overcoming Biological Barriers 23: Physico- chemical and Computational Approaches to Drug Discovery 24: Biomarkers for Traumatic Brain Injury 25: Drug Discovery from Natural Products 26: Anti- inflammatory Drug Discovery 27: New Therapeutic Strategies for Type 2 Diabetes: Small Molecules 28: Drug Discovery for Psychiatric Disorders View Online 29: Organic Chemistry of Drug Degradation 30: Computational Approaches to Nuclear Receptors 31: Traditional Chinese Medicine 32: Successful Strategies for the Discovery of Antiviral Drugs 33: Comprehensive Biomarker Discovery and Validation for Clinical 1 0 Application 0 P F 34: Emerging Drugs and Targets for Parkinson's Disease 1- 2 35: Pain Therapeutics; Current and Future Treatment Paradigms 4 6 1 36: Biotherapeutics: Recent Developments using Chemical and Molecular 0 8 8 Biology 7 1 8 37: Inhibitors of Molecular Chaperones as Therapeutic Agents 7 9 9/ 38: Orphan Drugs and Rare Diseases 3 10 39: Ion Channel Drug Discovery 0. 1 40: Macrocycles in Drug Discovery oi: d 41: Human- based Systems for Translational Research org | 42: Venoms to Drugs: Venom as a Source for the Development of Human sc. Therapeutics bs.r 43: Carbohydrates in Drug Design and Discovery u p s:// 44: Drug Discovery for Schizophrenia http 45: Cardiovascular and Metabolic Disease: Scientific Discoveries and New n Therapies o 19 46: Green Chemistry Strategies for Drug Discovery 0 y 2 47: Fragment- based Drug Discovery a M 48: Epigenetics for Drug Discovery 07 49: New Horizons in Predictive Drug Metabolism and Pharmacokinetics on 50: Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, d he Evaluation s bli 51: Nanomedicines: Design, Delivery and Detection u P 52: Synthetic Methods in Drug Discovery: Volume 1 53: Synthetic Methods in Drug Discovery: Volume 2 54: Drug Transporters: Role and Importance in ADME and Drug Development 55: Drug Transporters: Recent Advances and Emerging Technologies 56: Allosterism in Drug Discovery 57: Anti- aging Drugs: From Basic Research to Clinical Practice 58: Antibiotic Drug Discovery: New Targets and Molecular Entities 59: Peptide- based Drug Discovery: Challenges and New Therapeutics 60: Drug Discovery for Leishmaniasis 61: Biophysical Techniques in Drug Discovery 62: Acute Brain Impairment Through Stroke: Drug Discovery and Transla- tional Research 63: Theranostics and Image Guided Drug Delivery View Online 64: Pharmaceutical Formulation: The Science and Technology of Dosage Forms 65: Small- molecule Transcription Factor Inhibitors in Oncology 66: Therapies for Retinal Degeneration: Targeting Common Processes 67: Kinase Drug Discovery: Modern Approaches 1 0 68: Advances in Nucleic Acid Therapeutics 0 P F 69: MicroRNAs in Diseases and Disorders: Emerging Therapeutic Targets 1- 2 4 6 1 0 8 8 7 1 8 7 9 9/ 3 0 1 0. 1 oi: d g | or c. s s.r b u p s:// p htt n o 9 1 0 2 y a M 7 0 on d e h s bli u P How­to­obtain­future­titles­on­publication: A standing order plan is available for this series. A standing order will bring delivery of each new volume immediately on publication. For­further­information­please­contact: Book Sales Department, Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge, CB4 0WF, UK Telephone: +44 (0)1223 420066, Fax: +44 (0)1223 420247, Email: [email protected] Visit our website at www.rsc.org/books View Online MicroRNAs in Diseases and Disorders 1 Emerging Therapeutic Targets 0 0 P F 1- 2 4 6 1 0 8 8 7 1 78 Edited by 9 9/ 3 0 1 Philip V. Peplow 0. 1 oi: University­of­Otago,­New­Zealand d g | Email: [email protected] or c. s.rs Bridget Martinez b u Los­Alamos­National­Laboratory,­USA p s:// Email: [email protected] p htt n o George A. Calin 9 01 MD­Anderson­Cancer­Center,­USA 2 y Email: [email protected] a M 7 0 on and d e h blis Aurora Esquela- Kerscher u P Eastern­Virginia­Medical­School,­USA Email: [email protected] View Online 1 0 0 P F 1- 2 4 6 1 0 8 8 7 81 Drug Discovery Series No. 69 7 9 39/ Print ISBN: 978-1 - 78801- 394- 9 0 0.1 PDF ISBN: 978- 1- 78801-6 42- 1 oi:1 EPUB ISBN: 978- 1- 78801- 781- 7 d Print ISSN: 2041- 3203 org | Electronic ISSN: 2041- 3211 c. s s.r A catalogue record for this book is available from the British Library b u p s:// © The Royal Society of Chemistry 2019 p n htt All­rights­reserved o 9 1 Apart­from­fair­dealing­for­the­purposes­of­research­for­non-c­ommercial­purposes­or­for­ 0 2 y private­study,­criticism­or­review,­as­permitted­under­the­Copyright,­Designs­and­Patents­ a M Act­1988­and­the­Copyright­and­Related­Rights­Regulations­2003,­this­publication­may­ 7 0 not­be­reproduced,­stored­or­transmitted,­in­any­form­or­by­any­means,­without­the­prior­ on permission­in­writing­of­The­Royal­Society­of­Chemistry­or­the­copyright­owner,­or­in­ d he the­case­of­reproduction­in­accordance­with­the­terms­of­licences­issued­by­the­Copyright­ s bli Licensing­Agency­in­the­UK,­or­in­accordance­with­the­terms­of­the­licences­issued­by­the­ u P appropriate­Reproduction­Rights­Organization­outside­the­UK.­Enquiries­concerning­ reproduction­outside­the­terms­stated­here­should­be­sent­to­The­Royal­Society­of­­ Chemistry­at­the­address­printed­on­this­page. 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For further information see our web site at www.rsc.org Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon, CR0 4YY, UK 7 0 0 P F 1- Preface 2 4 6 1 0 8 8 7 1 8 7 9 9/ 3 0 1 MicroRNAs have been found to be associated with the development and 0. oi:1 progression of many different diseases and disorders. The increasing effort g | d devoted to understanding the roles of these molecules in the pathophysi- or ology of these conditions, together with identifying specific microRNAs as c. s.rs markers that can improve diagnostic and prognostic accuracy, and serve as ub indicators of response to therapy, has provided the impetus for the construc- p s:// tion of this book. p htt It is the goal of this book to provide a forum for clinical experts to pres- on ent recent data on the design and testing of drugs in relation to microR- 9 1 NAs, including drug targets and response, synthesis of microRNA mimics 0 2 y and inhibitors, preclinical studies, and clinical trials. It also brings together a M scientific experts to present the state of the art in their fields of health and 7 0 disease. It is my hope that the topics covered herein will provide new infor- d on mation on the role of microRNAs in diseases and disorders and that this e sh knowledge will lead to a more effective approach and clinical management ubli of these conditions. P I wish to express my deep appreciation to each of the chapter authors for the time and effort spent on writing informative reviews on their respective areas of clinical and research interest. Also I wish to express my gratitude to my co- editors Bridget Martinez, George Calin and Aurora Esquela-K erscher. Finally, I wish to thank the staff of the Royal Society of Chemistry for their help, support, and patience in the course of putting together this book. Philip V. Peplow   Drug Discovery Series No. 69 MicroRNAs in Diseases and Disorders: Emerging Therapeutic Targets   Edited by Philip V. Peplow, Bridget Martinez, George A. Calin and Aurora Esquela-K  erscher © The Royal Society of Chemistry 2019 Published by the Royal Society of Chemistry, www.rsc.org vii View Online 7 0 0 P F 1- 2 4 6 1 0 8 8 17 8 7 9 9/ 3 0 1 0. 1 oi: d g | or c. s s.r b u p s:// p htt n o 9 1 0 2 y a M 7 0 on d e h s bli u P 9 0 0 P F 1- Dedication 2 4 6 1 0 8 8 7 1 8 7 9 9/ 3 0 1 To the editors and chapter authors for their hard work to put together this 0. oi:1 exciting book summarizing the bright future ahead for non- coding RNAs in g | d translational medicine. Many thanks to members of the Esquela- Kerscher or laboratory and faculty, students and staff of the Leroy T. Canoles Jr. Cancer c. s.rs Research Center for their support and spirited discussions about how our ub research can better impact the cancer biology field and the community. p ps:// Aurora Esquela- Kerscher htt on This book is dedicated to our universe, which inspires, challenges, creates 9 1 and molds beauty, even from the most unexpected corners and circum- 0 2 y stances. The pursuit of knowledge is a great adventure. In loving memory of a M Elmer Martinez, my late father. Endless gratitude to my mother Eda Noguera, 7 0 my sister Karla “Zeo” Sanchez and my brother Elmer Martinez. on ed Bridget Martinez h s ubli To the many students, fellows, scientists and clinicians who contributed to P the extraordinary expansion of the field of non- coding RNA biology and med- icine. A special thanks to the past and present members of Calin's labora- tory. Without their dedication and hard work no discoveries or papers would come out of my laboratory. George A. Calin To my family, friends, staff and students at the Otago Medical School, thank you for your support and encouragement as I have travelled on my journey in teach- ing and biomedical research. And special thanks to you Bridget for shining your light on me in these past few years and helping me achieve so much more. Philip Peplow   Drug Discovery Series No. 69 MicroRNAs in Diseases and Disorders: Emerging Therapeutic Targets   Edited by Philip V. Peplow, Bridget Martinez, George A. Calin and Aurora Esquela-Kerscher © The Royal Society of Chemistry 2019 Published by the Royal Society of Chemistry, www.rsc.org ix 1 1 0 P F 1- Contents 2 4 6 1 0 8 8 7 1 8 7 9 9/ 3 0 1 Chapter 1 Role of Nutrition, the Epigenome, and MicroRNAs 0. oi:1 in Cancer Pathogenesis 1 g | d Zachary Cadieux, Holly Lewis and Aurora or Esquela- Kerscher c. s s.r ub 1.1 Introduction 1 p s:// 1.2 Epigenetic Link to Cancer 2 p htt 1.3 miRNAs are Closely Associated with on Human Cancer 3 9 1 1.3.1 miRNA Biogenesis is Complex 3 0 2 y 1.3.2 miRNAs as Tumor Suppressors and a M Oncogenic Factors 4 7 0 1.3.3 Extracellular Delivery of miRNAs 5 d on 1.4 miRNAs and the Epigenome 6 e sh 1.4.1 miRNAs that Regulate the Epigenetic ubli Machinery 7 P 1.4.2 miRNAs Targeted by the Epigenetic Machinery 10 1.5 miRNAs, Dietary Factors, and the Epigenome 11 1.5.1 Resveratrol 11 1.5.2 Ellagitannins and Ellagic Acid 13 1.5.3 Epigallocatechin- 3- gallate 13 1.5.4 Genistein 14 1.5.5 Curcumin 15 1.5.6 Diindolylmethane 17   Drug Discovery Series No. 69 MicroRNAs in Diseases and Disorders: Emerging Therapeutic Targets   Edited by Philip V. Peplow, Bridget Martinez, George A. Calin and Aurora Esquela-K  erscher © The Royal Society of Chemistry 2019 Published by the Royal Society of Chemistry, www.rsc.org xi