Role of multidrug resistance associated protein 4 (MRP4 ABCC4) in the resistance and toxicity of oxazaphosphorines

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Role of multidrug resistance associated protein 4 (MRP4 ABCC4) in the resistance and toxicity of oxazaphosphorines

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ROLE OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP4/ABCC4) IN THE IN VITRO ACTIVITY OF CYCLOPHOSPHAMIDE AND IFOSFAMIDE ZHANG JING (B.Med, School of Medicine, Zhejiang University, P.R. China) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2008 ƒ ACKNOWLEDGEMENTS I like to thank my former supervisor, Dr. Shufeng Zhou and my supervisor Prof Ho Chi Lui, Paul and co-supervisor Prof Ng Ka-Yun, Lawrence, for their great support, guidance and encouragement, for their invaluable assistance in the planning and conducting of the project, and for their advice when difficulties were encountered. I also like to thank Prof Tan May Chin, Theresa of the Department of Biochemistry, National University of Singapore for providing the MRP4 transfected HepG2 cell line, which was the focus of this project. I like to acknowledge the technical assistance given by all laboratory officers and students in my department and acknowledge the scholarship from the National University of Singapore and the generous support of the National University of Singapore Academic Research Funds. Finally, I want to make a special acknowledgement to my family for their great moral support. -i- ƒ PUBLICATIONS ARISING FROM THIS THESIS Referred Journal Papers 1. Zhang J, Ng LK, and Ho PC. Interaction of Oxazaphosphorine Anticancer Agents with Multidrug Resistance Associated Protein 4. Biochemical Pharmacology (under revision). 2. Tian Q, Zhang J, Chan E, Dun W, and Zhou SF. Multidrug resistance proteins (MRPs) and implication in drug development. Drug Development Research 2005; 64(1):1-18. 3. Tian Q, Zhang J, Tan TM, Chan E, Duan W, Chan SY, Boelsterli UA, Ho PC, Yang H, Bian JS, Huang M, Zhu YZ, Xiong WP, Li XT and Zhou SF. Human Multidrug Resistance Associated Protein Confers Resistance to Camptothecin Analogs. Pharmaceutical Research 2005; 22(11): 1837-1853. 4. Zhang J, Tian Q, Chan SY and Duan W, and Zhou SF. Insights into oxazaphosphorine resistance and possible approaches to its circumvention. Drug Resistance Updates 2005; 8(5): 271-297. 5. Zhang J, Tian Q, Chan SY, Duan W, Li SC, Zhu YZ, and Zhou SF. Metabolism and Transport of Oxazaphosphorines and the Clinical Implications. Drug Metabolism Reviews 2005; 37 (4):611-703. 6. Tian Q, Zhang J, Chan SY, Tan TM, Duan W, Huang M, Zhu YZ, Chan E, Yu Q, Nie YQ, Ho PC, Li Q, Ng LK, Yang HY, Hong W, Bian JS, and Zhou SF. Topotecan is a Substrate for Multidrug Resistance Associated Protein 4. Current Drug Metabolism 2006; 7(1): 105-118. - ii - 7. Zhang J, Tian Q, and Zhou SF. Clinical pharmacology of cyclophosphamide and ifosfamide. Current Drug Therapy 2006; 1(1):55-84. 8. Zhang J, Tian Q, and Zhou SF. Reversers for oxazaphosphorine resistance. Current Cancer Drug Targets 2006; 6(5): 385-407. Published Conference Abstracts 1. Zhang J, Tian Q, and Zhou SF. Resistance profiles of multidrug resistance associated protein to anticancer drugs. 17th Singapore Pharmacy Congress, 30 June-3 July 2005, Singapore. 2. Tian Q, Zhang J, Tan MQ, Chan E, Chan SY, and Zhou SF. Resistance profiles of camptothecins in HepG2 cells with overexpression of MRP4. 17th Singapore Pharmacy Congress, 30 June-3 July 2005, Singapore. 3. Suhaiemi TN, Zhang J, and Zhou SF. Multidrug resistance associated protein (MRP4) confers resistance to cyclophosphamide. 17th Singapore Pharmacy Congress, 30 June-3 July 2005, Singapore. 4. Zhang J, Tian Q, and Zhou SF. Resistance profiles of multidrug resistance associated protein to anticancer drugs. Inaugural AAPS-NUS Student Chapter Symposium, 16 September 2005, Singapore. 5. Tian Q, Zhang J, and Zhou SF. Multidrug resistance associated protein confers resistance to camptothecins. Inaugural AAPS-NUS Student Chapter Symposium, 16 September 2005, Singapore. 6. Tian Q, Zhang J, Tan MQ, Chan E, Chan SY, Duan W, and Zhou SF. Human multidrug resistance associated protein confers resistance to camptothecins. 1st - iii - Postgraduate Congress of Faculty of Science of NUS, 21-22 September 2005, Singapore - iv - ƒ TABLE OF CONTENTS ƒ  ACKNOWLEDGEMENTS I  ƒ  PUBLICATIONS ARISING FROM THIS THESIS . II  ƒ  TABLE OF CONTENTS . V  ƒ  SUMMARY . IX  ƒ  LIST OF TABLES . XII  ƒ  LIST OF FIGURES . XIII  ƒ  LIST OF ABBREVIATIONS . XV  CHAPTER 1  INTRODUCTION 1  1.1  MULTIDRUG RESISTANT ASSOCIATED PROTEINS (MRPS) 2  1.1.1  An overview of MRPs 2  1.1.2  The specific role of MRP4/ABCC4 11  1.2  CYCLOPHOSPHAMIDE AND IFOSFAMIDE . 17  1.2.1  Clinical activity and mechanism of action of cyclophosphamide and ifosfamide 17  1.2.2  Pharmacokinetics and pharmacodynamics of cyclophosphamide and ifosfamide 20  1.2.3  Drug resistance to cyclophosphamide and ifosfamide 29  1.3  OBJECTIVES . 33  CHAPTER 2  CONFIRMATION OF THE EXPRESSION AND FUNCTION OF MRP4/ABCC4 TRANSFECTED HEPG2 CELLS 35  2.1  INTRODUCTION 35  2.2  MATERIALS AND METHODS 36  2.2.1  Chemicals 36  2.2.2  Cell Culture . 37  2.2.3  Cytotoxicity assay in V/HepG2 and MRP4/HepG2 cells . 37  2.2.4  Western blot analysis . 38  2.2.5  Quantitative analysis of MRP4/ABCC4 expression by immunostaining . 39  -v- 2.2.6  Quantitative Real-time Polymerase Chain Reaction (PCR) 39  2.2.7  Statistical analysis . 40  2.3  RESULTS 40  2.3.1  Cytotoxicity assay 40  2.3.2  Western blot analysis . 43  2.3.3  Quantitative analysis of MRP4/ABCC4 expression by immunostaining . 44  2.3.4  Quantitative Real-time PCR 45  2.4  DISCUSSION . 46  CHAPTER 3  THE ROLE OF MRP4/ABCC4 ON THE CYTOTOXICITY OF CYCLOPHOSPHAMIDE AND IFOSFAMIDE IN HEPG2 CELLS 48  3.1  INTRODUCTION 48  3.2  MATERIALS AND METHODS 49  3.2.1  Chemicals 49  3.2.2  Cell Culture . 50  3.2.3  Cytotoxicity assay in V/HepG2 and MRP4/HepG2 cells . 50  3.2.4  Cytotoxicities of cyclophosphamide and ifosfamide in V/HepG2 and MRP4/HepG2 cells with different MRP4/ABCC4 inhibitors or GSH synthesis inhibitor . 50  3.2.5  Cytotoxicities of cyclophosphamide and ifosfamide in V/HepG2 and MRP4/HepG2 cells with MRP4/ABCC4 inducer . 51  3.2.6  Western blot analysis . 51  3.2.7  Quantitatove analysis of MRP4/ABCC4 expression by immunostaining 51  3.2.8  Statistical analysis . 51  3.3  RESULTS 52  3.3.1  Cytotoxicity assay 52  3.4  DISCUSSION . 72  CHAPTER 4  THE EFFECT OF MUTANT MRP4/ABCC4 ON THE CYTOTOXICITY OF CYCLOPHOSPHAMIDE AND IFOSFAMIDE IN HEPG2 CELLS 76  - vi - 4.1  INTRODUCTION 76  4.2  MATERIALS AND METHODS . 78  4.2.1  Chemicals 78  4.2.2  Cell culture 78  4.2.3  Cytotoxicity assay in V/HepG2 and MRP4/HepG2 cells . 79  4.2.4  Statistical analysis . 79  4.3  RESULTS 79  4.3.1  Cytotoxicity assay 79  4.4  DISCUSSION . 86  CHAPTER 5  INDUCING POTENCY OF CYCLOPHOSPHAMIDE AND IFOSFAMIDE ON THE MRP4/ABCC4 EXPRESSION 88  5.1  INTRODUCTION 88  5.2  MATERIALS AND METHODS . 89  5.2.1  Chemicals 89  5.2.2  Cell culture 89  5.2.3  Western blot analysis . 89  5.2.4  Quantitatove analysis of MRP4/ABCC4 expression by immunostaining 90  5.2.5  Real-time PCR . 90  5.2.6  Statistical analysis . 90  5.3  RESULTS 90  5.3.1  Western blot analysis . 90  5.3.2  Quantitative analysis of MRP4/ABCC4 expression by immunostaining . 94  5.3.3  Real-time PCR . 96  5.4  DISCUSSION . 98  CHAPTER 6  CONCLUSIONS AND FUTURE DIRECTIONS . 102  6.1  CONCLUSIONS 102  6.2  THESIS ACHIEVEMENTS 105  6.3  FUTURE DIRECTIONS 106  - vii - ƒ  BIBLIOGRAPHY 108  - viii - ƒ SUMMARY Multidrug resistance associated protein (MRP4/ABCC4) is an organic anion pump capable of transporting nucleoside, nucleotide analogs and cyclic nucleotide. Increased expression of MRP4/ABCC4 in tumor cells is associated with resistance to various chemotherapeutic agents such as methotrexate (MTX), topotecan and others. MRP4/ABCC4 is identified as the contributor of multidrug resistance (MDR). The oxazaphosphorines including cyclophosphamide (CP) and ifosfamide (IF), represent an important group of therapeutic agents due to their substantial antitumor and immuno-modulating activity. Resistance to oxazaphosphorines is a major clinical problem often resulting in therapeutic failure. Detailed investigations aimed at identification of resistant proteins and circumventing approaches of intrinsic drug resistance are thus warranted. The aim of this study was to investigate the resistance profiles of MRP4/ABCC4 to oxazaphosphorines including CP and IF in the absence and presence of various MRP4/ABCC4 inhibitors or MRP4/ABCC4 inducers by using the MRP4/ABCC4 overexpressing HepG2 cells. 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Mol Cell Endocrinol 2003;205:169-84. - 126 - [...]... explore the effect of MRP4/ABCC4 on the transport of oxazaphosphorines and CFB It would also be interesting to investigate the effect of the combination of oxazaphosphorines and -x- MRP4/ABCC4 inhibitors on cancer treatment, and to investigate the effect of MRP4/ABCC4 on the toxicity of CFB - xi - LIST OF TABLES Table 1-1 Reported Substrates and Inhibitors for MRPs 9  Table 2-1 Drug sensitivity of. .. basolaterally in polarized cells depending on the cell type The basolateral location of MRP4/ABCC4 protein was observed in the tubuloacinar cells of prostate [69], hepatocytes [78], the choroid plexus epithelium, and the ductular epithelial cells of pancreas [87] In contrast, the apical location of MRP4/ABCC4 protein was found in the proximal tubule of human kidney [86], and the endothelial cells of the brain... modulators including sildenafil and trequinsin are not only the high-affinity inhibitors of MRP5/ABCC5, but also potent inhibitors of MRP4/ABCC4 [68] Furthermore, the inhibitors of nucleoside transport including dipyridamole, dilazep, and nitrobenzyl mercaptopurine riboside (NBMPR) also can inhibite MRP4/ABCC4 [68] Moreover, the cellular efflux of cGMP by both MRP4/ABCC4 and MRP5/ABCC5 is inhibited by PGA1 and. .. cephalosporins including ceftizoxime, cefazolin, cefmetazole, and cefotaxime had been identified as substrates of MRP4/ABCC4 In addition, MRP4/ABCC4 is involved in the luminal efflux of of ceftizoxime and cefazolin in the kidney by in vivo pharmacokinetic studies using MRP4 knock out mice [77] - 13 - MRP4/ABCC4 overexpressed NIH3T3 cells showed significantly increased resistance to MTX in short-term... cells after these cells were incubated with media containing different concentration of oxazaphosphorines including CP and IF The MRP4/ABCC4 inducer CFB was used as a positive control The present study showed that the positive control CFB can up-regulate MRP4/ABCC4 expression at protein level in HEK293 cells In addition, CP significantly increased the MRP4/ABCC4 expression at both protein level and mRNA... concentrations [102] In addition, Ci et al found that most of the injectable cephalosporins are inhibitor of MRP4/ABCC4, except for cefepime, cefsulodin, and cephaloridine, while - 15 - aminocephalosporins have a weak inhibitory effect on MRP4/ABCC4 [77] Although a variety of inhibitors of MRP4/ABCC4 has been identified, there are no specific inhibitors of MRP4/ABCC4 MRP4/ABCC4 may be regulated at... used in the clinical treatment, CP was shown to have antitumor activity in murine models in the early 1 940 s and shortly after it was introduced to clinical cancer chemotherapy [113] IF was developed in the middle of the 1960s and introduced in clinical practice in the early 1970s [1 14] CP is a widely used alkylating agent in the treatment for haematological malignancies and a variety of solid tumors, including... inhibitors of OAT such as probenecid, and sulfinpyrazone can inhibit the transport activities of MRP4/ABCC4 [76] Like MRP1/ABCC1 and MRP2/ABCC2, MRP4/ABCC4 is also inhibited by the leukotriene D4 receptor antagonist MK571 [78] The flavonoid, genistein was demonstrated a strong inhibitor of MRP4/ABCC4 mediated transport of PMEA in the MRP4/ABCC4 -overexpressing microglia cells [79] In addition, the phosphodiesterase...overexpressing HepG2 cells when compared with MRP4/ABCC4 overexpressing HepG2 cells This demonstrates that CP and IF are highly possible substrates of MRP4/ABCC4 and GSH may play an important role in the resistance to CP and IF mediated by MRP4/ABCC4 Oxazaphosphorines may also have effects on the expression of MRP4/ABCC4 This was investigated by detecting MRP4/ABCC4 expression in HEK293 cells and HepG2... MRP5/ABCC5 is inhibited by PGA1 and PGE1, the steroid progesterone and the anticancer drug estramustine (a combination of estrogen and mechlorethamine) [101] PGF1α, PGF2α, PGA1, and TXB2 are high-affinity inhibitors of MRP4/ABCC4 -mediated transport of PGE1 and PGE2 [75] Various NSAIDs including indomethacin, indoprofen, ketoprofen, and flurbiprofen inhibited MRP4/ABCC4 mediated E217βG transport at physiologically . interesting to investigate the effect of the combination of oxazaphosphorines and - xi - MRP4/ABCC4 inhibitors on cancer treatment, and to investigate the effect of MRP4/ABCC4 on the toxicity of. circumventing approaches of intrinsic drug resistance are thus warranted. The aim of this study was to investigate the resistance profiles of MRP4/ABCC4 to oxazaphosphorines including CP and IF in the. and IF in the 48 -hr drug- exposure assays. In MRP4/ABCC4 overexpressing HepG2 cells, the presence of the MRP4/ABCC4 inhibitors including diclofenac, MK571, and celecoxib decreased the cytotoxicity

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