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THE ISOLATION and BIOLOGICAL EVALUATION of ANTI-INFLAMMATORY and CHEMOPREVENTIVE TRITERPENOID NATURAL PRODUCTS by EMILY CLEGG BA

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THE ISOLATION and BIOLOGICAL EVALUATION of ANTI-INFLAMMATORY and CHEMOPREVENTIVE TRITERPENOID NATURAL PRODUCTS by EMILY CLEGG BA THE ISOLATION AND BIOLOGICAL EVALUATION OF ANTI-INFLAMMATORY AND CHEMOPREVENTIVE TRITERPENOID NATURAL PRODUCTS By EMILY CLEGG BARKER Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Thesis Advisors: Gregory P. Tochtrop, Ph.D. and John J. Letterio, M.D. Department of Chemistry CASE WESTERN RESERVE UNIVERSITY May, 2015 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Emily C. Barker Candidate for the Doctor of Philosophy degree* (signed) ___________________________Dr. Michael G. Zagorski (Committee Chair) ___________________________Dr. Rajesh Viswanathan ___________________________Dr. John J. Mieyal ___________________________Dr. John J. Letterio ___________________________Dr. Gregory P. Tochtrop (date) ___________________________May 20, 2014 *We also certify that written approval has been obtained for any proprietary material contained therein I dedicate this work to my Parents. Thank you for teaching by word and by example what it means to “Stick to your task ‘til it sticks to you.” Table of Contents Table of Contents ................................................................................................................. i List of Tables ..................................................................................................................... iv List of Figures ......................................................................................................................v Acknowledgements .......................................................................................................... viii List of Abbreviations ...........................................................................................................x Abstract ............................................................................................................................ xvi Chapter 1: Introduction ........................................................................................................1 1.1 Natural products in medicine .....................................................................................1 1.1.1 History of natural products in medicine through the 19th century ......................1 1.1.2 Natural products in medicine during the recent century .....................................3 1.2 Triterpenoids ..............................................................................................................5 1.2.1 Natural triterpenoid, bryonolic acid ....................................................................8 1.2.2 Natural triterpenoid, celastrol .............................................................................9 1.2.3 Potential of triterpenoids in cancer chemoprevention ......................................10 1.3 Cancer chemoprevention .........................................................................................13 1.3.1 The cancer burden .............................................................................................14 1.3.2 Chemoprevention background ..........................................................................15 1.3.3 Progress and success in cancer chemoprevention .............................................17 1.4 Carcinogenesis .........................................................................................................18 1.4.1 Inflammation in carcinogenesis ........................................................................19 1.4.2 Colorectal cancer: a model example for inflammation-driven carcinogenesis .23 i 1.5 Cellular pathways as targets for chemoprevention ..................................................25 1.5.1 NF-κB and pro-inflammatory signaling ...........................................................26 1.5.2 Nrf2 and cytoprotective signaling .....................................................................27 1.5.3 Nrf2 historical background ...............................................................................28 1.5.4 Nrf2 as a target for chemoprevention ...............................................................33 1.6 Scope of this work ...................................................................................................39 1.7 References ................................................................................................................41 Chapter 2: Bryonolic Acid: A Large-Scale Isolation and Evaluation of Heme Oxygenase 1 expression in Activated Macrophages ............................................................................64 2.1 Introduction ..............................................................................................................64 2.2 Results and discussion .............................................................................................65 2.3 Experimental methods .............................................................................................73 2.4 Acknowledgement ...................................................................................................77 2.5 Bryonolic acid NMR spectra ..................................................................................79 2.6 References ................................................................................................................82 Chapter 3: Selection and Screening of Anti-inflammatory Herbal Extracts ......................86 3.1 Introduction ..............................................................................................................86 3.2 Results and discussion .............................................................................................87 3.3 Conclusions ..............................................................................................................95 3.4 Experimental methods .............................................................................................96 3.5 Acknowledgements ..................................................................................................99 3.6 References ..............................................................................................................100 ii Chapter 4: Natural Triterpenoid, Celastrol, as an Anti-inflammatory, Inducer of Cytoprotective Gene Expression and Chemopreventive in Colon Cancer .....................104 4.1 Introduction ............................................................................................................104 4.2 Results and Discussion ..........................................................................................107 4.3 Conclusion .............................................................................................................123 4.4 Experimental methods ...........................................................................................126 4.5 Acknowledgements ................................................................................................132 4.6 References ..............................................................................................................133 Chapter 5: Future Directions and Project Summary ........................................................141 5.1 Validation of celastrol as chemopreventive in colitis-associated colon cancer ....141 5.2 Further exploration of the active natural triterpenoids ..........................................144 5.3 Identification of Keap1 as a cellular target of celastrol .........................................147 5.4 Project summary and impact ..................................................................................149 5.5 Acknowledgements ................................................................................................151 5.6 References ..............................................................................................................152 Appendix ..........................................................................................................................155 A.1 Cell viability in RAW 264.7 cells treated with celastrol ......................................155 A.2 Cell viability in RAW 264.7 cells treated with celastrol and LPS .......................156 A.3 Cell viability in Peritoneal Macrophages treated with celastrol ..........................157 A.4 Cell viability in Peritoneal Macrophages treated with celastrol and LPS ............158 A.5 Gross necropsy statistics for in vivo study in Smad4co/co;Lck-crep27Kip1-/- (DKO) mice ......................................................................................................................................159 Bibliography ....................................................................................................................160 iii List of Tables Table 3.1: Concentrations of Extracts Resuspended in DMSO ........................................98 Table 4.1: Primer sequences used for probes in qRT-PCR .............................................131 iv List of Figures Figure 1.1: Triterpenoid Biosynthesis ................................................................................7 Figure 1.2: Pentacyclic Triterpenoids Relevant to this Thesis .........................................10 Figure 1.3: Carcinogenesis and Inflammation in Carcinogenesis ....................................22 Figure 1.4: Pro-inflammatory NFκB Pathway .................................................................27 Figure 1.5: Cytoprotective and Antioxidant Signaling Pathway ARE/Nrf2/Keap1 .........33 Figure 1.6: Nrf2-inducing Molecules Showing Clinical
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