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The Potential Inhibitory Effect of Dihomo-Gamma-Linolenic Acid on Colon Cancer Cell Growth Via Free Radical Metabolites in Cyclo

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The Potential Inhibitory Effect of Dihomo-Gamma-Linolenic Acid on Colon Cancer Cell Growth Via Free Radical Metabolites in Cyclo THE POTENTIAL INHIBITORY EFFECT OF DIHOMO-GAMMA-LINOLENIC ACID ON COLON CANCER CELL GROWTH VIA FREE RADICAL METABOLITES IN CYCLOOXYGENASE-CATALYZED PEROXIDATION A Dissertation Submitted to the Graduate Faculty of the North Dakota State University of Agriculture and Applied Science By Yan Gu In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Major Department: Pharmaceutical Sciences August 2012 Fargo, North Dakota North Dakota State University Graduate School Title THE POTENTIAL INHIBITORY EFFECT OF DIHOMO-GAMMA-LINOLENIC ACID ON COLON CANCER CELL GROWTH VIA FREE RADICAL METABOLITES IN CYCLOOXYGENASE-CATALYZED PEROXIDATION By YAN GU The Supervisory Committee certifies that this disquisition complies with North Dakota State University’s regulations and meets the accepted standards for the degree of DOCTOR OF PHILOSOPHY SUPERVISORY COMMITTEE: Dr. Steven Qian Chair Dr. Jagdish Singh Dr. Benedict Law Dr. Erxi Wu Dr. Clifford Hall Approved: 11/06/2012 Jagdish Singh Date Department Chair ABSTRACT Cyclooxygenase (COX) can metabolize dihomo-γ-linolenic acid (DGLA) and arachidonic acid (AA) through free radical-mediated lipid peroxidation to form the anti- carcinogenic 1-series of prostaglandins and pro-carcinogenic 2-series of prostaglandins, respectively. Our previous studies had demonstrated that in ovine COX-mediated DGLA and AA peroxidation, there are common and exclusive free radicals formed through different free radical reactions. However, it was still unclear whether the differences are associated with the contrasting bioactivity of DGLA vs. AA. In order to investigate the possible association between cancer cell growth and the exclusive free radicals generated from COX/DGLA vs. COX/AA, we refined our combined spin-trapping/LC/MS method with solid phase extraction to characterize free radicals in their reduced forms in the human colon cancer cell line HCA-7 colony 29, which has a high COX-2 expression. For the first time, we were able to profile free radical formation in the experimental settings in which cell proliferation (via MTS assay) and cell cycle distribution (via PI staining) could be assessed. Our results showed that DGLA- and AA-derived exclusive free radicals, rather than prostaglandins, were closely associated with the opposing bioactivities of DGLA vs. AA. Due to rapid conversion from DGLA to AA via Δ-5 desaturase (D5D), the anti- proliferative effect of DGLA on cancer cell growth was limited. Thus, double doses of DGLA and D5D inhibitor were introduced. Among DGLA, double-dose DGLA, and combined DGLA/D5D inhibitor treatments, the latter exerted the most anti-proliferative effect on cancer cell growth and caused significant cell G2/M arrest. D5D knockdown cells (via siRNA transfection) were used to further investigate the possible mechanism underlying the anti- proliferative effect of DGLA on cancer cell growth. In addition, the combined DGLA/D5D iii inhibitor treatment increased the susceptibility of cancer cells to the chemotherapy drug 5- fluorouracil. In D5D knockdown cells, DGLA and 5-fluorouracil exerted greater effects on cell growth inhibition and cytotoxicity due to synergism. In summary, increasing DGLA and concurrently decreasing AA in cells could be a novel approach to controlling the development of AA-dependent cancer. Our study allowed us to directly study the free radical-associated PUFA bioactivity, thus improving our understanding of COX-catalyzed lipid peroxidation in cancer biology. iv ACKNOWLEDGMENTS It is a pleasure to thank the many people who made this thesis possible. It is difficult to overstate my gratitude to my Ph.D. supervisor, Dr. Steven Qian. With his enthusiasm, his inspiration, and immense knowledge, he helped to make research fun for me. Throughout my thesis-writing period, he provided encouragement, sound advice, and lots of good ideas. I would have been lost without him. I would like to thank members of my graduate committee, Dr. Jagdish Singh, Dr. Benedict Law, Dr. Erxi Wu and Dr. Clifford Hall, for their guidance and suggestions. I am grateful to the secretaries, Janet and Jean, in the pharmaceutical science department, for assisting me in many different ways. I am indebted to the whole department of pharmaceutical sciences for providing a stimulating and fun environment in which to learn and grow. I am especially grateful to my labmates and people who helped me with my experiments, Qingfeng Yu, Yi Xiao, Yonghua Yang, Susan Zhong, Evan Eide, Preeti Purwaha and Yi Xu. I wish to thank my friends Jing Zhang, Shuang Zhou, Hui Xu, Fanrong Yao, Chengluan Xuan, Wen Yan and Yue Li at NDSU for helping me get through the difficult times, and for all the emotional support, encouragement, entertainment, and caring they provided. I wish to thank my entire extended family for providing a loving environment for me, especially my fiancé, Yin Wan, for supporting and encouraging me to pursue this degree. Without his encouragement, I would not have finished the degree. Lastly, and most importantly, I wish to thank my parents, Qiusong Gu and Lixia Ni. They bore me, raised me, supported me, taught me, and loved me. To them I dedicate this thesis. v TABLE OF CONTENTS ABSTRACT……………………………………………………………………………………...iii ACKNOWLEDGMENTS.………...…………………………………………………..……….....v LIST OF TABLES………………………………………..……………………………...……….xi LIST OF FIGURES……………………………………………………..……………………….xii LIST OF SCHEMES……………………………………………..………………..……………xiv LIST OF ABBREVIATIONS.………………………………………….…………………….….xv CHAPTER 1. INTRODUCTION……………………………………….………………………...1 1.1. Polyunsaturated Fatty Acids, Eicosanoids and Inflammation Related Diseases.…1 1.1.1. Metabolism of dietary polyunsaturated fatty acids…..……….……..…….1 1.1.2. AA-derived eicosanoids and inflammation related diseases……………...6 1.1.3. DGLA-derived eicosanoids and inflammation related diseases………..…8 1.2. Lipid Peroxidation and Lipid Mediators in Inflammatory Diseases…….……….12 1.3. The Catalytic Mechanism of COX……………………..………………………..16 1.4. PUFA-Derived Free Radical’s Detection and Characterization……….…...……20 1.4.1. Electron spin resonance and spin-trapping……………...……………….20 1.4.2. Development of the combined HPLC/ESR/MS and spin-trapping technique…………………………………………………………………23 1.4.3. Detection of free radical from COX-catalyzed AA and DGLA peroxidation via spin-trapping and LC/ESR/MS………………………...26 1.4.4. Refining the approach to ESR spin trapping and LC/MS to detect free radicals under normal biological conditions……………...………….…..27 CHAPTER 2. METERIALS AND METHODS……………………..….……………………….31 2.1. Chemicals and Reagents………………………………………………..………..31 2.2. Cell Culture……………………………………………………...……………….33 vi 2.3. Preparation of Reaction Solution…………………..……………………..……...34 2.3.1. Stock solutions…………………………………………………………...34 2.3.2. Cell lysis buffer…………………………………………………………..34 2.3.3. Protein assay……………………………………………………………..35 2.3.4. SDS-polyacrylamide gel electrophoresis (SDS-PAGE)…………………36 2.3.5. Immunoblotting…………………………………………………………..38 2.3.6. Cell cycle distribution……………………………………………………38 2.3.7. Transfection with siRNA…………………………………...……………39 2.4. Spin-Trapping Experiments in Cell-PBS Suspension…………...……..………...39 2.5. Spin-Trapping Experiments under Normal Cell Growth Conditions…..………..39 2.6. Extraction and Analysis of Hydroxylamine………………………..…………….40 2.7. Spin-Trapping of Hydroxyethyl Radical (Test of POBN’s Trapping Ability).….41 2.8. Extraction and Analysis of PUFAs and PGEs in Cell Culture Medium…....……42 2.9. Offline ESR………………………………………………………………………42 2.10. LC/MS and LC/MS2……………………………………………………………..43 2.10.1. LC/MS and LC/MS2 for identification of free radical adducts and hydroxylamines…………………………………………………………..43 2.10.2. LC/MS for quantification of hydroxylamine…………………………….44 2.10.3. LC/MS for PUFAs and PGEs detection and quantification……………...45 2.11. Transfect HCA-7 Colony 29 Cells with FADS1 siRNA………………………...45 2.12. Western Blot Analysis………………………………………………..………….46 2.13. Cell Proliferation Assay via MTS………………..………………….......……….48 2.14. Cell Cycle Distribution Analysis via PI Staining….…………………………….49 2.15. Statistics………………………………………………………………………….50 vii CHAPTER 3. DETECTION AND IDENTIFICATION OF FREE RADICALS FORMED FROM CELLULAR COX-CATALYZED AA AND DGLA PEROXIDATION………51 3.1. Introduction………………………………………………………………………51 3.2. Results and Discussion………………………………………………...………...56 3.2.1. COX-2 expression in HCA-7 colony 29 cells……………………………56 3.2.2. Offline ESR detection of free radicals…………………………………...56 3.2.3. LC/ESR/MS identification of free radicals in cell-PBS suspension…..…58 3.2.4. Assessment of POBN’s trapping ability…………………………………61 3.2.5. LC/MS and dual spin-trapping in detection of free radicals as hydroxylamines…………………………………….…………………….63 3.2.6. LC/MS, LC/MS2 and dual spin-trapping in characterization of hydroxylamines…………………………………………………………..66 CHAPTER 4. THE ASSOCIATION BETWEEN AA-/DGLA-DERIVED FREE RADICAL METABOLITES AND COLON CANCER CELL GROWTH………………………….74 4.1. Introduction………………………………………………………………………74 4.2. Results and Discussion……………………………………………...…………...75 4.2.1. Quantification of hydroxylamines as free radicals in a single dose of PUFA treatment…..………….…………………..……………...….……75 4.2.2. Profile of PUFAs and PGEs in a single dose of PUFA treatment….……80 4.2.3. Effect of PUFAs on cell proliferation and cell cycle distribution……….84 4.2.4. Comparison of effects of free radical metabolites and PGEs on cell growth……………………………………………………………………86 4.2.5. Study of double doses of PUFA treatment……..………………………..91 CHAPTER 5. INHIBITION OF THE CONVERSION FROM DGLA TO AA ATTENUATED
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