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THE EFFECTS of INDIRUBIN DERIVITIVES on GENE EXPRESSION and CELLULAR FUNCTIONS in the MURINE MACROPHAGE Abigail Babcock Clemson University, [email protected]

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THE EFFECTS of INDIRUBIN DERIVITIVES on GENE EXPRESSION and CELLULAR FUNCTIONS in the MURINE MACROPHAGE Abigail Babcock Clemson University, Asbabco@Clemson.Edu Clemson University TigerPrints All Dissertations Dissertations 8-2008 THE EFFECTS OF INDIRUBIN DERIVITIVES ON GENE EXPRESSION AND CELLULAR FUNCTIONS IN THE MURINE MACROPHAGE Abigail Babcock Clemson University, [email protected] Follow this and additional works at: https://tigerprints.clemson.edu/all_dissertations Part of the Biology Commons Recommended Citation Babcock, Abigail, "THE EFFECTS OF INDIRUBIN DERIVITIVES ON GENE EXPRESSION AND CELLULAR FUNCTIONS IN THE MURINE MACROPHAGE" (2008). All Dissertations. 277. https://tigerprints.clemson.edu/all_dissertations/277 This Dissertation is brought to you for free and open access by the Dissertations at TigerPrints. It has been accepted for inclusion in All Dissertations by an authorized administrator of TigerPrints. For more information, please contact [email protected]. THE EFFECTS OF INDIRUBIN DERIVATIVES ON GENE EXPRESSION AND CELLULAR FUNCTIONS IN THE MURINE CELL LINE, RAW 264.7 A Dissertation Presented to the Graduate School of Clemson University In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Biological Sciences by Abigail Sue Babcock August 2008 Accepted by: Dr. Charles D. Rice, Committee Chair Dr. Lyndon L. Larcom Dr. Thomas R. Scott Dr. Alfred P. Wheeler ABSTRACT Indirubin is the active ingredient in the ancient herbal remedy, Danggui Longhui Wan, which is used as an anti-leukemic, anti-inflammatory, and detoxification treatment. Indirubin-3’-monoxime (IO) is the most widely studied of the indirubin derivatives. Most have been shown to inhibit cyclin-dependent kinases and glycogen synthase kinases, triggering cell cycle arrest and apoptosis with different levels of activity depending on the particular structure. These kinases inhibited by indirubin(s) play key roles in cellular proliferation and immune functions, therefore synthetic indirubins may have significant applications as therapeutic agents for cancer, inflammation, and neurological diseases. Indirubin is also a potent aryl hydrocarbon receptor (AhR) agonist. The AhR is a cytosolic protein, which upon ligand binding is translocated to the nucleus and acts as a transcription factor for genes involved in drug metabolism, oxidative stress, and inhibitors of the cell cycle. Known anthropogenic ligands (PCBs, dioxins, PAHs etc.) are mutagenic, carcinogenic, and immunotoxic. In this study, I examined the effects of select indirubins on gene/protein expression profiles, AhR activation, and cellular functions in the mouse macrophage cell line RAW 264.7. Structure activity relationships (SAR) show that different derivatives of indirubin may differentially affect AhR activation, kinase inhibition, and/or other cellular functions, including intracellular killing of bacteria. The ultimate goal was to identify a synthetic indirubin derivative that would be beneficial to cancer and inflammation research without being overtly toxic. ii From this research, Indirubin-3’-(2,3 dihydroxypropyl)-oximether) (E804), and 6-bromoindirubin-3-monoxime (BIO) were shown to be very potent AhR ligands with strong anti-inflammatory properties. This study also shows that E804 has more clinical promise than its more famous counterpart indirubin-3’- monoxime. iii DEDICATION I dedicate this dissertation to my parents Joe and Sue Babcock. I could not have gotten through these last 4 years without your love, support, and unwavering belief in me. I feel very blessed to have the best parents in the world, who instilled in me the confidence, morality, and perseverance I needed to succeed. I further dedicate this work to my brothers, Taylor and Joey, my grandparents, family and friends. You have been a great support system for which I am grateful. iv ACKNOWLEDGEMENTS I would like to first acknowledge my advisor and mentor, Dr. Charlie Rice, who set the bar high and had the confidence I would reach it. Your love of science is contagious, your knowledge impressive, and your humor hilarious. I will take with me all your stories and “advice”. I have the deepest respect and appreciation for you and my time here. I would also like to thank my graduate committee members, Lyn Larcom, Tom Scott, and Hap Wheeler for your expertise, guidance, and belief in me. Thank you for the knowledge I received from your classes and the example you set as great scientists. I would like to thank my former labmates, Marlee Beckham Marsh, Laura Hunt, Shannon Billings, Moss Matsebatlela, Palllavi Vedantam, and Josephine Woydyl. I am so grateful for your knowledge, patience, and hard work over the last four years; you all have truly made my time here wonderful. Tim, I could not have made it through this time without your love, support, and understanding. I want to especially thank you for all the slushes that kept me going. You are my best friend and I feel very blessed to have such a great man in my life. To my ALIVE crew, thank you for all the prayers, laughs, and shoulders to cry on. Your friendships are invaluable to me. Finally, thank you to Sara and Jason for spoiling me when I needed it the most. v TABLE OF CONTENTS TITLE PAGE ......................................................................................................i ABSTRACT....................................................................................................... ii DEDICATION................................................................................................... iv ACKNOWLEDGEMENTS .................................................................................v LIST OF TABLES............................................................................................ vii LIST OF FIGURES ......................................................................................... iX LITERATURE REVIEW ....................................................................................1 INTRODUCTION ............................................................................................21 MATERIALS AND METHODS ........................................................................31 RESULTS .......................................................................................................42 DISCUSSION..................................................................................................80 APPENDIX......................................................................................................89 REFERENCES CITED..................................................................................124 vi LIST OF TABLES Table Page 1 Functional gene groupings of the Mouse Stress and Toxicity Pathway Finder™ RT 2 Profiler™ PCR Array ...............................................................................51 2 Altered inflammatory gene expression in RAW 264.7 macrophages treated for 24 hours with LPS, Io, E804, or PCB-126........................................................52 3 Altered inflammatory gene expression in RAW 264.7 macrophages treated simultaneously with LPS and Io, E804, or PCB-126 for 24 hours..............................53 4 Altered proliferation and carcinogenesis gene expression in RAW 264.7 macrophages treated for 24 hours with LPS, Io, E804, or PCB-126 ................................................54 5 Altered proliferation and carcinogenesis gene expression in RAW 264.7 macrophages treated simultaneously with LPS and Io, E804, or PCB-126 for 24 hours ......................55 6 Altered growth arrest and senescence gene expression in RAW 264.7 macrophages treated for 24 hours with LPS, Io, E804, or PCB-126 ................................................56 7 Altered growth arrest and senescence gene expression in RAW 264.7 macrophages treated simultaneously with LPS and Io, E804, or PCB-126 for 24 hours ......................57 vii List of Tables (Continued) Page 8 Altered apoptosis gene expression in RAW 264.7 macrophages treated for 24 hours with LPS, Io, E804, or PCB-126 ................................................58 9 Altered apoptosis gene expression in RAW 264.7 macrophages treated simultaneously with LPS and Io, E804, or PCB-126 for 24 hours ....................................................................................59 10 Altered stress related gene expression in RAW 264.7 macrophages treated for 24 hours with LPS, Io, E804, or PCB-126 ................................................60 11 Altered stress related gene expression in RAW 264.7 macrophages treated simultaneously with LPS and Io, E804, or PCB-126 for 24 hours ....................................................................................61 viii LIST OF FIGURES Figure Page 1 Structure of indirubin derivatives..........................................................13 2 Dual mechanisms in which indirubins my induce cell cycle arrest .........................................................................29 3 Comparison of indirubins and TCDD in their interactions in two AhR reporter systems and two kinase assays............................................................................30 4 Cytotoxicity of compounds to RAW 246.7 cells....................................47 5 Cytotoxicity of compounds to rat glioma D74 cells...............................48 6 Effects of 1 µM of compounds on apoptosis in RAW 246.7 macrophages .........................................................49 7 Effects of 1 µM of compounds with LPS on apoptosis in RAW 246.7 macrophages......................................................50 8 Nuclear translocation of AhR in RAW 246.7 cells treated with media control for 4 hours .......................................62
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