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Siramesine and Lapatinib Induce Synergic Cell Death Via a Ferroptotic Mechanism in Lung Adenocarcinoma and Glioblastoma Cells

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Siramesine and Lapatinib Induce Synergic Cell Death Via a Ferroptotic Mechanism in Lung Adenocarcinoma and Glioblastoma Cells SIRAMESINE AND LAPATINIB INDUCE SYNERGIC CELL DEATH VIA A FERROPTOTIC MECHANISM IN LUNG ADENOCARCINOMA AND GLIOBLASTOMA CELLS by Anna R. Blankstein A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba in partial fulfillment of the requirements of the degree of MASTER OF SCIENCE Department of Biochemistry and Medical Genetics University of Manitoba Winnipeg, Manitoba Copyright © 2017 by Anna R. Blankstein ABSTRACT In cancer cells, the most common forms of cell death are often actively inhibited, contributing to the development of drug resistance. Identifying and exploiting alternative cell death pathways are essential to overcoming or bypassing drug resistance. Ferroptosis, a newly described, morphologically and biochemically distinct, cell death mechanism is characterized by iron-dependent cellular accumulation of reactive oxygen species. The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor (TKI), synergistically induced death in breast cancer cells. This cell death had characteristics of ferroptosis: it was blocked by the ferroptosis inhibitor ferrostatin-1 and the iron chelator deferoxamine. The objective of the present study was to determine whether lysosome disruptors and TKIs, in combination, would induce synergic cell death via a ferroptotic mechanism in lung adenocarcinoma and glioblastoma cells. Inducing ferroptosis could be a potential therapeutic strategy for these cancers that have limited available treatment options. ii “The central therapeutic challenge of the newest cancer medicine, then, was to find, among the vast numbers of similarities in normal cells and cancer cells, subtle differences in genes, pathways, and acquired capabilities—and to drive a poisoned stake into that new [Achilles’] heel.” Siddhartha Mukherjee The Emperor of All Maladies iii ACKNOWLEDGEMENTS I would like to thank my supervisor, Dr. Spencer Gibson, for giving me the opportunity to pursue first my Honour’s project, and then this Master’s research project in his lab, and for providing me with mentorship at every stage. I would also like to express my gratitude to my committee members, Dr. Mark Nachtigal and Dr. Afshin Raouf, who have given their time, and expert guidance as I progressed through my program. I acknowledge the Terry Fox Research Institute and CIHR for their financial support of my research through graduate studentships. I would like to thank Elizabeth Henson for her time in teaching me the required techniques, for her encouragement, guidance, and humour. I would like to acknowledge all the past and present members of the Gibson lab for giving me experimental advice and creating a welcoming and stimulating work environment. Particularly I want to acknowledge Dr. Shumei Ma who set the groundwork for my project. Also, I would like to thank Sara Kost for her help with the isobolograms and combination analyses. I must also thank Dr. Donna Wall for offering me a summer student position when I was an undergraduate student, and giving me my first experience of laboratory-based research. I learned flow cytometry techniques in her laboratory, and have been able to put that knowledge to good use during the present project. Finally, I am grateful to my friends and family for ongoing nutritional and grammatical support. iv TABLE OF CONTENTS ABSTRACT ................................................................................................................................... ii ACKNOWLEDGEMENTS ........................................................................................................ iv TABLE OF CONTENTS ............................................................................................................. v LIST OF TABLES ..................................................................................................................... viii LIST OF FIGURES ..................................................................................................................... ix LIST OF ABBREVIATIONS ...................................................................................................... x CHAPTER 1: INTRODUCTION ................................................................................................ 1 1.1 CANCER IN CANADA ...................................................................................................... 1 1.2 HALLMARKS OF CANCER ............................................................................................ 1 1.3 GLIOBLASTOMA ............................................................................................................. 2 1.4 LUNG ADENOCARCINOMA .......................................................................................... 5 1.5 IRON HOMEOSTASIS IN HEALTH AND DISEASE .................................................. 8 1.5.1 Iron Regulation ............................................................................................................ 10 1.5.2 Iron and Disease ........................................................................................................... 15 1.5.3 Iron and Cancer ............................................................................................................ 18 1.6 CELL DEATH .................................................................................................................. 22 1.6.1 Necrosis ........................................................................................................................ 22 1.6.2 Necroptosis .................................................................................................................. 23 1.6.3 Apoptosis ..................................................................................................................... 23 1.6.4 Autophagy .................................................................................................................... 24 1.6.5 Ferroptosis.................................................................................................................... 25 1.6.5.1 Ferroptosis and Development ............................................................................... 31 1.6.5.2 Ferroptosis and Disease ........................................................................................ 32 1.6.5.3 Ferroptosis and Cancer ......................................................................................... 32 CHAPTER 2: RATIONALE, HYPOTHESIS AND RESEARCH AIMS ............................. 34 2.1 RATIONALE .................................................................................................................... 34 2.2 HYPOTHESIS .................................................................................................................. 35 2.3 RESEARCH AIMS ........................................................................................................... 35 CHAPTER 3: MATERIALS AND METHODS ...................................................................... 36 3.1 REAGENTS ...................................................................................................................... 36 3.2 CELL CULTURE ............................................................................................................. 36 3.2.1 Passaging of Cells ........................................................................................................ 37 3.2.2 Preservation of Cells .................................................................................................... 37 3.2.3 Thawing of Cells .......................................................................................................... 37 3.2.4 Cell Counting ............................................................................................................... 38 v 3.4 MEMBRANE PERMEABILITY ASSAY FOR TOTAL CELL DEATH .................. 40 3.5 PRUSSIAN BLUE STAINING AND BRIGHTFIELD MICROSCOPY .................... 40 3.6 MEASUREMENT OF INTRACELLULAR LABILE IRON USING CALCEIN-AM ................................................................................................................................................... 41 3.7 DHE STAINING FOR Reactive Oxygen Species .......................................................... 41 3.8 C11-BODIPY STAINING FOR LIPID PEROXIDATION .......................................... 42 3.9 PREPARATION OF CELL LYSATES ......................................................................... 42 3.10 PROTEIN ELECTROPHORESIS AND WESTERN BLOTTING .......................... 43 3.11 ASSESSMENT OF DRUG INTERACTION ............................................................... 45 3.12 STATISTICAL ANALYSIS .......................................................................................... 46 CHAPTER 4: RESULTS ........................................................................................................... 47 4.1 AIM 1: To determine whether lysosome targeting agents and tyrosine kinase inhibitors induce synergic cell death in lung adenocarcinoma and glioblastoma cells .... 47 4.1.1 Determination of optimal doses of siramesine and lapatinib ....................................... 47 4.1.2 Determination of optimal incubation times for cells treated with siramesine and lapatinib ................................................................................................................................. 49 4.1.3 Siramesine and lapatinib induce synergic cell death in glioblastoma and lung adenocarcinoma cells ...........................................................................................................
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