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Darshini Thesis (April-30).Pdf Evaluating the dopaminergic neurotoxic effects of chemotherapeutics By Darshini Desai A Thesis submitted to the Graduate Faculty of Auburn University in partial fulfillment of the requirements for the Degree of Master of Science Auburn, Alabama May 05, 2018 Approved by Muralikrishnan Dhanasekaran, Co-chair, Professor of Pharmacology Robert Rusty Arnold, Professor of Pharmacology Satyanarayana Pondugula, Associate Professor of Anatomy Physiology and Pharmacology Vishnu Suppiramaniam, Professor of Pharmacology (Doxorubicin, dopaminergic toxicity, cyclophosphamide, chemotherapy) Copyright 2018 by Darshini Desai Table of Contents Abstract………………………………………..……………………………………..…………. v Acknowledgments……………………………………………………………………..…………vi List of Tables……………………………………………………………………………………vii List of Illustrations……………………………………………………………………………...viii List of Abbreviation……………………………………………………………..........................xi Chapter 1: Introduction and Literature review ............................................................................. 1 1.0 Introduction to the chemotherapeutics ........................................................................ 2 2.1 Alkylating agents ..................................................................................................... 5 2.2 Plant alkaloids ......................................................................................................... 20 2.3 Antimetabolites ......................................................................................................... 33 2.4 Antibiotics ................................................................................................................. 36 2.5 Topoisomerase inhibitors .......................................................................................... 54 2.6 Miscellaneous class ................................................................................................... 62 ii Chapter 2: Materials and methods 3.0 Chemical and reagents ............................................................................................. 74 3.1 Treatment design ....................................................................................................... 75 3.2 Cytotoxicity Assay .................................................................................................... 76 3.3 Protein Quantification ............................................................................................... 77 3.4 Quantifying Reactive Oxygen species ....................................................................... 77 3.5 Catalase activity ......................................................................................................... 78 3.6 Mitochondrial Complex-I Activity ............................................................................ 78 3.7 Mitochondrial Complex-IV Activity ......................................................................... 78 3.8 Monoamine oxidase (MAO) activity ......................................................................... 79 3.9 Nitrite assay ............................................................................................................... 80 3.10 Superoxide Dismutase Activity ............................................................................... 80 3.11 Glutathione content .................................................................................................. 80 3.12 Glutathione peroxidase activity ............................................................................... 81 3.13 Lipid peroxidation .................................................................................................... 81 3.14 Quantitative RT-PCR ................................................................................................ 82 iii 3.15 Statistical analysis ..................................................................................................... 82 Chapter 3: Results 4.1 Doxorubicin and cyclophosphamide induced Dose-Dependent and Time-Dependent reduction in N27 Cell viability: ............................................................................................................. 83-85 4.2 Doxorubicin and cyclophosphamide increases ROS generation .......................................... 86 4.3 Doxorubicin and cyclophosphamide increases nitrite content .............................................. 87 4.4 Doxorubicin increases Glutathione peroxidase activity ....................................................... 88 4.5 Doxorubicin decreases Catalase activity .............................................................................. 89 4.6 Cyclophosphamide and doxorubicin increases Monoamine oxidase activity (MAO) ......... 90 4.7 Effect of doxorubicin and cyclophosphamide on Mitochondrial Complex-I activity and Complex- IV activity: Mitochondrial Complex-I activity and Complex- IV activity: ............... 91 4.8 Doxorubicin and cyclophosphamide increases Superoxide dismutase activity: ................... 92 4.9 Doxorubicin increases Lipid peroxide formation ................................................................. 93 4.10 Cyclophosphamide and doxorubicin decreases Glutathione content .................................. 94 4.11 Cyclophosphamide and doxorubicin increases BAX expression and MAO-B expression ................................................................................................................................................ 95-96 Discussion ........................................................................................................................... 97-103 iv References .......................................................................................................................... 103-137 v Abstract Chemotherapy-induced neurotoxicity is one of the most common contraindication seen in the cancer survivors. Thus chemotherapy-induced neurotoxicity can adversely affect the clinical management of these patients. Cancer survivors during chemotherapy often complain about problems with memory retrieval, learning and concentration, which may persevere even post- treatment or never fully resolve. Role of chemotherapeutics in hippocampal neurotoxicity is well established and is referred to as chemobrain or chemofog. However, there are very few reports on the chemotherapeutics-induced neurotoxicity in movement disorders like Parkinson’s disease. Hence, in this study we used dopaminergic cell lines (N27) to investigate the cytotoxic effects of doxorubicin and cyclophosphamide. N27 cells have been well established in studies of dopamine biosynthesis, neurotoxicity and used as a dopaminergic model for in vitro studies. In this study the dopaminergic neurotoxicity was evaluated in N27 cells using MTT assay. The effect of doxorubicin and cyclophosphamide were studied on markers of oxidative stress, mitochondrial functions and other relevant neurotoxic mechanisms. All statistical analyses were performed using the Prism-V software (La Jolla, CA, USA). All data were expressed as Mean ± SEM. Statistical analyses were performed using one-way analysis of variance (ANOVA) followed by an appropriate post-hoc test including Tukey's and Dunnett's method ((p < 0.05) was considered to indicate statistical significance). Doxorubicin significantly induced dopaminergic neurotoxicity. Thus, if careful patient care measures are not taken with cancer survivors exposed to doxorubicin and cyclophosphamide, it can considerably increase the risk for several movement disorders. vi Acknowledgments I would like to thank first and foremost to my advisory Dr. Muralikrishnan Dhanasekaran, for his patience and guidance in helping me overcoming the problems I faced during the experiments and research. I would also like to thank my committee members Dr. Vishnu, Dr. Arnold and very thankful to Dr. Satya for always supporting me and motivating me. I would also like to thank my Lab members Kodye Abbott, Mohammed Almagrabhi, Jenna Bloemer, Priyanka Das for always supporting me and creating positive environment around me to work efficiently. Last but not the least I am very much thankful to my parents for supporting me and always pushed me for pursuing the higher studies. I am very much thankful for my uncle who supported me financially without which my master’s studies wouldn’t have been possible. vii List of Tables Table 1a-1c Effect of alkylating agents …………………………………………..……….24-27 Table 2a-2c Effect of Plant alkaloids ………………………………..…………………….37-39 Table 3a-3c Effect of Antimetabolites………….………………………………………….47-51 Table 4a-4c Effect of antitumor antibiotics………………..………………………………57-62 Table 5a-5c Effect of topoisomerase inhibitors……………………………………………68-70 viii List of Illustrations Figure 1 History of chemotherapeutics related neurotoxicity…………………………………..12 Figure 4.1 a- 4.1 e Doxorubicin and cyclophosphamide induced Dose-Dependent and Time- Dependent dopaminergic neurotoxicity (N27 neuronal death)………….......……………….89-92 Figure 4.2 Doxorubicin and cyclophosphamide increases ROS generation………………….....94 Figure 4.3 Doxorubicin and cyclophosphamide increases nitrite content………………….…...95 Figure 4.4 Doxorubicin increases Glutathione peroxidase activity ………......………….……...95 Figure 4.5 Doxorubicin decreases Catalase activity ……………………….............…………...96 Figure 4.6 Cyclophosphamide and doxorubicin increases Monoamine oxidase activity (MAO)...........................................................................................................................................97 Figure 4.7a- 4.7
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