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CYTOTOXICITY of Se-LABELED ANTIBODIES and SELENOFOLATE AGAINST TRIPLE NEGATIVE BREAST CANCER CELL LINES MDA-MB-231 and MDA-MB-468

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CYTOTOXICITY of Se-LABELED ANTIBODIES and SELENOFOLATE AGAINST TRIPLE NEGATIVE BREAST CANCER CELL LINES MDA-MB-231 and MDA-MB-468 CYTOTOXICITY OF Se-LABELED ANTIBODIES AND SELENOFOLATE AGAINST TRIPLE NEGATIVE BREAST CANCER CELL LINES MDA-MB-231 AND MDA-MB-468 By Soni Khandelwal B.Sc., B.Ed., M.Sc. A Dissertation in NUTRITIONAL SCIENCES Submitted to the Graduate Faculty of Texas Tech University in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Approved Dr. Julian E. Spallholz Co-Chair of Committee Dr. Lauren S. Gollahon Co-Chair of Committee Dr. Nikhil Dhurandhar Dr. Mallory L. Boylan Dr. Ruth Serra-Moreno Dr. Mark Sheridan Dean of the Graduate School May, 2018 Copyright 2018, Soni Khandelwal Texas Tech University, Soni Khandelwal, May 2018 ACKNOWLEGDEMENTS There have been many people who have walked alongside me during the last four years. They have guided me, placed opportunities in front of me and showed me the doors that might be beneficial to open. I am truly grateful to each and every one of them. I would like to thank my research co-advisors, Dr. Julian E. Spallholz and Dr. Lauren S. Gollahon for their enduring support, patience, guidance and advice through this project. They have been a constant source of motivation which has helped me to build positive attitude during these years. Special thanks to Dr. Boylan for believing in my abilities and introducing me to Dr. Spallholz. Exchanging conversations with Dr. Boylan have helped me to remain engrossed on my path. Today, if I am able complete this research project it is because of Dr. Nikhil Dhurandhar, who helped us arrange funds for the research. Dr. Dhurandhar always helped me whenever I needed one and made sure the research continued to progress towards a finished dissertation. I would like to thank Dr. Serra-Moreno for valuable insights and experiences on Western Blot, which incented me to widen my research from various perspectives. Whenever I had question, I knew Dr. Serra-Moreno would have answers to those questions. Besides my committee members, I appreciate Dr. Gilbert Kirsh for synthesizing Selenofolate and providing me with the compound during the entire study period. I would like to express my sincere gratitude to the College of Human Sciences and Department of Nutritional Sciences for providing the financial support of this study. I would also like to extend my gratitude to the Faculty and Staff of Department of Nutritional Sciences and Biological Sciences. My appreciation is extended to the doctoral and undergraduate students Caroline, Sergio, Drake, Noshin, Maliha, Zahid, Shao-Hua, Samudani, Sanjoy, Sagor, Belinda, Stacy, Maria and Roberto for their help, friendship and stimulation discussion. I would like to thank Shane Scoggin for his suggestions for ii Texas Tech University, Soni Khandelwal, May 2018 alternatives while conducting my experiments. I would also extend my gratitude to my friends- Anuradha, Arwa, Nadeeja, Pooja, Priyanka, Sneha, Sriporna, Swati and Shwetha and would like to thank them for their unconditional support throughout the study. I am most grateful to my family in India and my husband Mr. Rahul Khandelwal who has played a key role in shaping my career and helped me achieve my goals with patience and focus. iii Texas Tech University, Soni Khandelwal, May 2018 TABLE OF CONTENTS ACKNOWLEGDEMENTS ................................................................................................. ii ABSTRACT ...................................................................................................................... viii LIST OF TABLES .............................................................................................................. ix LIST OF FIGURES ............................................................................................................. x LIST OF ABBREVIATIONS ....................................................................................... xxviii I. INTRODUCTION ............................................................................................................ 1 GENERAL CHARACTERISTICS OF CANCER ................................................................ 1 BREAST CANCER ........................................................................................................... 2 ETIOLOGY AND RISK FACTORS ................................................................................... 2 CLASSIFICATION OF BREAST CANCERS ..................................................................... 4 STAGES OF BREAST CANCER ....................................................................................... 6 TREATMENT FOR BREAST CANCER ............................................................................ 8 TRIPLE NEGATIVE BREAST CANCER ........................................................................ 11 SELENIUM: ESSENTIAL AND TOXIC MICRONUTRIENT ........................................... 12 MAJOR FUNCTIONS OF SELENIUM IN THE HUMAN BODY ..................................... 13 DISEASES ASSOCIATED WITH SELENIUM DEFICIENCY ......................................... 15 SELENIUM TOXICITY .................................................................................................. 16 MECHANISM OF TOXICITY OF SELENIUM ................................................................ 17 SELENIUM IN CANCER PREVENTION ........................................................................ 20 TARGETED THERAPY .................................................................................................. 22 PROPOSAL AND GOALS .............................................................................................. 24 HYPOTHESIS ................................................................................................................ 25 SPECIFIC AIMS ............................................................................................................. 25 II. CYTOTOXICITY OF FOLATE, SELENOFOLATE AND SELENITE AGAINST TRIPLE NEGATIVE BREAST CANCER CELL LINES MDA-MB-231 AND MDA-MB- 468 ..................................................................................................................................... 26 ABSTRACT .................................................................................................................... 26 KEYWORDS .................................................................................................................. 27 iv Texas Tech University, Soni Khandelwal, May 2018 INTRODUCTION ........................................................................................................... 27 MATERIALS AND METHODS ...................................................................................... 29 Materials ..................................................................................................................... 29 Synthesis of 1-propanol selenocyanate ........................................................................... 29 Synthesis of Selenofolate .............................................................................................. 30 Cell Culture ................................................................................................................. 31 Detection of Superoxide In Vitro: Selenofolate ............................................................... 32 Detection of Intracellular Reactive Oxygen Species Accumulation In Situ: Superoxide Generation Assay ......................................................................................................... 32 Optimization of Cell Density for Treatment ................................................................... 32 Cell Treatments ............................................................................................................ 33 Visual Assessments of Cellular Morphology .................................................................. 34 Cell Viability Measured by Trypan Blue Exclusion ........................................................ 34 Experimental Cell Cultures ........................................................................................... 35 MTT Assay .................................................................................................................. 35 MitoTracker® Red and Annexin V Staining ................................................................... 36 Western Blotting .......................................................................................................... 37 STATISTICAL ANALYSES ............................................................................................ 38 RESULTS AND DISCUSSION ........................................................................................ 41 III. CYTOTOXICITY OF AVASTIN®, SELENOAVASTIN AND SELENITE AGAINST TRIPLE NEGATIVE BREAST CANCER CELL LINES MDA-MB-231 AND MDA-MB- 468 ..................................................................................................................................... 71 ABSTRACT .................................................................................................................... 71 KEYWORDS .................................................................................................................. 72 INTRODUCTION ........................................................................................................... 72 MATERIALS AND METHODS ...................................................................................... 74 Materials ..................................................................................................................... 74 Monoclonal antibodies ................................................................................................
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