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Mrp1/Abcc1) Potentiates Doxorubicin-Induced Cardiotoxicity in Mice

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University of Kentucky UKnowledge Theses and Dissertations--Toxicology and Cancer Biology Toxicology and Cancer Biology 2015 LOSS OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 1 (MRP1/ABCC1) POTENTIATES DOXORUBICIN-INDUCED CARDIOTOXICITY IN MICE Wei Zhang University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Zhang, Wei, "LOSS OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 1 (MRP1/ABCC1) POTENTIATES DOXORUBICIN-INDUCED CARDIOTOXICITY IN MICE" (2015). Theses and Dissertations--Toxicology and Cancer Biology. 12. https://uknowledge.uky.edu/toxicology_etds/12 This Doctoral Dissertation is brought to you for free and open access by the Toxicology and Cancer Biology at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Toxicology and Cancer Biology by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Wei Zhang, Student Dr. Mary Vore, Major Professor Dr. Isabel Mellon, Director of Graduate Studies LOSS OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 1 (MRP1/ABCC1) POTENTIATES DOXORUBICIN-INDUCED CARDIOTOXICITY IN MICE DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School at the University of Kentucky By Wei Zhang Lexington, KY Co-Director: Dr. Mary Vore, Professor of Toxicology and Dr. Daret St Clair, Professor of Toxicology University of Kentucky Lexington, KY 2015 Copyright © Wei Zhang, 2015 ABSTRACT OF DISSERTATION LOSS OF MRP1 POTENTIATES DOXORUBICIN-INDUCED CARDIOTOXICITY IN MICE Doxorubicin (DOX) is a broad-spectrum and effective chemotherapeutic agent, but its use in oncologic practice is limited by dose-dependent cumulative cardiotoxicity. DOX-induced cardiotoxicity is in large part due to its ability to cause oxidative stress. Multidrug resistance associated protein 1 (MRP1/ABCC1) is a member of the ATP-binding cassette (ABC) transporter superfamily. By effluxing a wide variety of endogenous and exogenous substrates, Mrp1 plays important physiological roles in multiple tissues and also protects normal tissues against toxicants. However, the role of MRP1 in heart is largely unknown. The role of Mrp1 in DOX-induced cardiotoxicity was investigated in Mrp1 null (Mrp1-/-) and their C57BL (WT) littermates. Chronic DOX caused body weight loss and hemotoxicity, and these adverse effects were significantly exacerbated in Mrp1-/- vs WT mice. Importantly, loss of Mrp1 potentiated DOX-induced cardiotoxicity, presenting as worsened cardiac function and more cellular apoptosis in DOX treated Mrp1-/- mice. Mrp1 also protected neonatal mouse cardiomyocytes (CM) and cardiac fibroblasts (CF) culture against DOX cytotoxicity in vitro. This was demonstrated by the decreased cell survival, more apoptosis and more DNA damage in DOX treated Mrp1-/- vs WT cells. In addition, the effects of deletion of Mrp1 was studied on glutathione (GSH)/glutathione disulfide (GSSG) homeostasis, glutathione conjugate of 4- hydroxy-2-nonenal (GS-HNE) accumulation, protein oxidative damage and expression of antioxidant enzymes. Loss of Mrp1 led to significantly higher GSH and GSSG basal levels in heart. Following DOX treatment, Mrp1-/- CM and CF showed increased GSH and GSSG levels vs WT cells. Meanwhile, DOX increased expression of the GSH synthesis enzymes in Mrp1-/- but not WT cells. Thus, increased GSH synthesis may contribute to the further increase in the GSH pool in DOX-treated Mrp1-/- cells. DOX induced comparable increases of GS-HNE concentration in WT and Mrp1-/- mice hearts. Finally, expression of extracellular superoxide dismutase (ECSOD/SOD3) was significantly lower in Mrp1-/- vs. WT CM treated with either saline or DOX. In summary, this study is the first to document a protective role of Mrp1 in DOX-induced cardiotoxicity. It gives critical information regarding the potential adverse sequelae of introduction of MRP1 inhibitors as adjuncts to clinical chemotherapy of multidrug resistant tumors. KEYWORDS: Mrp1, doxorubicin, cardiotoxicity, glutathione, GS-HNE. Wei Zhang Student’s signature 08/10/2015 Date LOSS OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 1 (MRP1/ABCC1) POTENTIATES DOXORUBICIN-INDUCED CARDIOTOXICITY IN MICE By Wei Zhang Dr. Mary Vore Co-Director of Dissertation Dr. Daret St Clair Co-Director of Dissertation Dr. Isabel Mellon Director of Graduate Studies 08/10/2015 Date Acknowledgements This project throughout my graduate training would not have been possible without the support of many people. First, I express my deepest thanks to my Ph.D. advisor, Professor Dr. Mary Vore, for providing me this wonderful opportunity to work in her laboratory and learn from her how to be a better scientist and a better person. Throughout my Ph.D. study, she always encouraged me to develop independent thinking and research skills. She continually and greatly assisted me with the scientific writing skills. I will always be grateful for the time, patience, attention, guidance, mentorship and support she has provided. I have my special thanks to the Co-chair of my committee Dr. Daret St Clair, who provided timely and instructive comments and evaluation at every stage of my research process, allowing me to complete this project successfully. I would like to acknowledge my committee members, Dr. Allan Butterfield and Dr. Zhigang Wang for their constructive comments, help and guidance. I am also grateful for Dr. Jonathon Satin for agreeing to be my outside examiner. I appreciate the assistance of Dr. Andrew Morris and Dr. Manjula Sunkara with LC/MS assays, Dr. Brandon Fornwalt, Dr. Moriel Vandsburger and Dr. Ahmed Abdel-Latif with the echocardiography study, Dr. Jonathon Satin and Gail Sievert with the neonatal mouse cardiomyocytes isolation, Dr. Chi Wang with the statistical analysis, and Dr. Mihail Mitov and Michael Alstott with the slot blot assay. I would also like to thank Dr. Xianglin Shi, Dr. Joy Zhang, Dr. Bernhard iii Hennig forgenerously providing experimental materials and instruments used in this study. I am grateful to the members of Dr. Vore’ Lab and Dr. St Clair’ lab, past and present, for all of their generous help, scientific advice, friendship and company. They are Baoxiang Yan, Dr. Jun Deng, Dr. Donna Coy, Dr. Tianyong Zhao, Dr. Paiboon Jungsuwadee, Dr. Caixia Hou, Teresa Noel, Dr. Luksana Chaiswing, Chontida Yarana, Dr. Yanming Zhao and Dr. Sangjit K Dhar. All my friends and colleagues at the University of Kentucky will be sorely missed. Finally, I am forever grateful to my parents, Yu Zhang and Jun Cai for their love and always encouraging me to pursue higher education. And last, but not least, I owe special thanks to my husband, Xiabin Chen, for his continuous love, encouragement and support through our time in Kentucky. iv TABLE OF CONTENTS Acknowledgements .............................................................................................. iii LIST OF TABLES ................................................................................................ vii LIST OF FIGURES ............................................................................................. viii Chapter One: Introduction Overview ........................................................................................................... 1 Doxorubicin (DOX) ............................................................................................ 3 DOX and its medical use in cancer treatment ................................................ 3 DOX induces cardiotoxicity ............................................................................ 3 Mechanisms of DOX-induced cardiotoxicity ................................................... 5 Current treatment for DOX induced cardiotoxicity .......................................... 8 ATP-binding cassette (ABC) transporter superfamily ...................................... 10 ABC transporter subfamilies and structure ..................................................
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