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The Role of Bile Acids in Overcoming Resistance to Chemotherapy By The Role of Bile Acids in Overcoming Resistance to Chemotherapy by Simon Chewchuk A thesis submitted as a partial fulfillment of the Requirements for the degree of Doctor of Philosophy (Ph.D.) in Biomolecular Sciences The Faculty of Graduate Studies Laurentian University Sudbury, Ontario, Canada © Simon Chewchuk, 2017 ii Abstract: In the context of cancer therapy, resistance to chemotherapy agents is a serious threat to patient welfare. In these circumstances, patients can either present with cancers that are naturally resistant to conventional therapy, referred to as innate resistance, or with cancers that become resistant following treatment, referred to as acquired resistance. In this thesis, we address the phenomenon of acquired drug resistance, involving cell lines selected for resistance to the anthracycline, doxorubicin. In the first study, we examined the role of the aldo-keto reductases AKR1C3 and AKR1B10 in doxorubicin resistance, enzymes that can hydroxylate doxorubicin to a less toxic form (doxorubicinol). Additionally, these enzymes can function to promote estrogen biosynthesis from estrone, which can have significant effects on cell growth and survival. We demonstrated in the first study that AKR1C3 and AKR1B10 are expressed at higher levels in doxorubicin resistant MCF-7 cells than their isogenic control counterparts. This change in expression correlated very well with increased estrogen synthesis. siRNA-mediated reduction in AKR1C3 and/or AKR1B10 transcript expression had no major effect on doxorubicin resistance, suggesting that these enzymes are not sufficient to mediate the doxorubicin resistance phenotype and that other mechanisms of doxorubicin resistance exist in these cells. We did, however, note that a pharmacological inhibitor of AKR enzymes (a bile acid termed β-cholanic acid) was effective in reversing doxorubicin resistance in doxorubicin-selected cell lines. This prompted a second study to investigate the mechanism for this reversal. We observed that β-cholanic acid strongly reduced doxorubicin resistance in cell lines that express the ABC transporter ABCC1, including doxorubicin-resistant MCF-7 breast tumour cells and H-69 lung cancer cells. Reversal of doxorubicin resistance was also observed in HEK293 cells transfected with ABCC1 expression vectors. Subsequent experiments confirmed that β-cholanic acid and another bile acid iii that does not inhibit the aldo-keto reductases was able to inhibit ABCC1-mediate doxorubicin efflux from tumour cells, thereby providing a mechanism for the reversal of doxorubicin resistance. Bile acids thus represent an important new class of compounds that could prove useful in improving the effectiveness of doxorubicin chemotherapy in cancer patients, specifically in recurrent tumours overexpressing the ABCC1 transporter. iv Acknowledgements I would like to take this time to acknowledge all those who have made it possible for me to reach this stage in my academic/professional career. I would like to begin by thanking my supervisor, Dr. Amadeo Parissenti, for taking a chance by accepting me as a graduate student. His guidance, generosity and patience have been a great influence in my life and have taught me much about the realities of working in research fields. I would also like to thank my committee member, Dr. Rob Lafrenie, whose lunch time discussions were instrumental in helping me design and troubleshoot experiments to further my research project. I would also like to thank the remaining members of my advisory committee: Dr. Tom Kovala, and Dr. Eric Gautier, for their support, encouragement and feedback on my various projects. Special thanks go to our technologists Ms. Stacey Hembruff, Dr. Stacey Santi and Dr. Baoqing Guo for teaching me most of the laboratory techniques employed in this thesis. In particular I would like to thank Dr. Guo for his assistance in generating the AKR1C3 plasmids used in this report. In addition Dr. Santi contributed data towards understanding the expression levels of BCL-2 in our resistant cell lines, as well as assisted in statistical analyses. Thanks to our collaborator Dr. Susan Cole of Queens University, Kingston Ontario, for generously providing not only advice regarding the project, but also 4 cell lines without which I would not have been able to complete the work presented here. I would like to thank all members of the Parissenti lab group past and present who supported me in this undertaking over the past several years: Dr. Jason Sprowl, Dr. Kerry Reed, Adam Tam, Aoife Cox, Jon Mapletoft, Derek Edwardson, Tyler Boorman, Dr. Twinkle Massilamani, Rashmi Narendrula, Samantha Innocent, and Amanda Fluke who all provided great insights and suggestions for my project during our weekly lab meetings. I would like to thank all of the members of the research department at the North Eastern Ontario Regional Cancer Center (now v called Health Sciences North Research Institute) for making the work environment so friendly and enjoyable. I would like to thank the North Eastern Ontario Regional Cancer Center for use of their wonderful laboratory facilities. I would like to thank the Northern Cancer Research Foundation for their financial support through the invaluable scholarship programs they provide. I would like to thank my sister Christina whose own professional success has been an inspiration to me to keep pushing forward and following my dreams wherever that may take me. Finally I would like to thank my parents for their endless support for me and all my efforts as I try to find my way through this stage of my life, the completion of my Doctorate in Biomolecular Sciences, and on to the next. vi Table of Contents Abstract: ....................................................................................................................................... iii Acknowledgements ....................................................................................................................... v Table Of Contents ....................................................................................................................... vii List Of Figures.............................................................................................................................. xi List Of Tables ............................................................................................................................. xiii List Of Abbreviations ................................................................................................................ xiv List Of Publications .................................................................................................................. xvii Chapter 1 ....................................................................................................................................... 1 Introduction ............................................................................................................................... 1 1.1: Cancer .............................................................................................................................. 1 1.2: Breast Cancer.................................................................................................................. 3 1.3: Treatment Of Breast Cancer ......................................................................................... 5 1.4: Anthracyclines ................................................................................................................ 6 1.5: Chemotherapy Resistance In Breast Cancer ............................................................... 8 1.6: Hypotheses And Specific Aims .................................................................................... 11 1.7: References ..................................................................................................................... 12 Chapter 2 ..................................................................................................................................... 19 Resistance To Anthracyclines And Taxanes In Breast Cancer .......................................... 19 2.1: Contributions By Authors: .......................................................................................... 20 Chapter 3 ..................................................................................................................................... 59 Role Of Drug Metabolism In The Cytotoxicity And Clinical Efficacy Of Anthracyclines ................................................................................................................................................... 59 3.1: Author Contributions ................................................................................................... 60 Chapter 4 ................................................................................................................................... 118 Background/Rationale For Studies On Estrogen Signalling Pathway ............................. 118 4.1: Introduction ................................................................................................................ 119 4.2: Hypothesis And Specific Aims Of Study 1 ............................................................... 124 4.3: References ................................................................................................................... 125 Chapter 5 ................................................................................................................................... 129 Alterations In Estrogen Signalling
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