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Reversal of multidrug resistance by novel polyoxypregnane compounds.

Chai, Stella. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 108-126). / Abstracts in English and Chinese. / ABSTRACT --- p.i / 論文摘要 --- p.iii / ACKNOWLEDGEMENTS --- p.v / PATENT AND PUBLICAION --- p.vii / CONFERENCE ABSTRACTS AND PRESENTATIONS --- p.viii / AWARDS --- p.ix / ABBREVIATIONS --- p.x / LIST OF TABLES --- p.xii / LIST OF FIGURES --- p.xiv / TABLE OF CONTENT --- p.xviii / Chapter CHAPTER 1. --- INTRODUCTION --- p.1 / Chapter 1.1 --- Multidrug resistance (MDR) --- p.1 / Chapter 1.1.1 --- Cancer --- p.1 / Chapter 1.1.2 --- Mechanisms of MDR in cancer --- p.1 / Chapter 1.1.2.1 --- Drug entry --- p.3 / Chapter 1.1.2.2 --- Drug metabolism --- p.3 / Chapter 1.1.2.3 --- Drug sequestration --- p.4 / Chapter 1.1.2.4 --- Mechanisms activated after nuclear entry --- p.5 / Chapter 1.1.2.5 --- Evasion of drug-induced apoptosis --- p.5 / Chapter 1.1.3 --- Approaches in treating MDR --- p.5 / Chapter 1.1.3.1 --- Overcoming MDR by inhibiting transporters --- p.6 / Chapter 1.1.3.2 --- Overcoming MDR by altering signaling pathway --- p.6 / Chapter 1.1.4 --- ATP Binding Cassette (ABC) Transporters --- p.7 / Chapter 1.1.4.1 --- P-glycoprotein (P-gp) --- p.7 / Chapter 1.1.4.2 --- Multidrug resistance-associated protein 1 (MRP 1) --- p.9 / Chapter 1.1.4.3 --- Breast cancer resistant protein (BCRP) --- p.10 / Chapter 1.1.4.4 --- ABC drug transporters and drug absorption --- p.11 / Chapter 1.2 --- The Use of Traditional Chinese Medicine (TCM) in circumventing P-gp-mediated MDR --- p.12 / Chapter 1.2.1 --- Active ingredients in TCM - Alkaloid --- p.12 / Chapter 1.2.2 --- Active ingredients in TCM - Saponin --- p.14 / Chapter 1.2.3 --- Active ingredients in TCM - Flavonoid --- p.15 / Chapter 1.2.4 --- Active ingredients in TCM - Others --- p.17 / Chapter 1.3 --- Polyoxypregnane compounds (POPs) --- p.17 / Chapter 1.3.1 --- Characterization --- p.17 / Chapter 1.3.2 --- POPs isolated from M. tenacissima --- p.18 / Chapter 1.4 --- Objectives of Current Study --- p.22 / Chapter CHAPTER 2. --- EFFECTS OF POLYOXYPREGNANE COMPOUNDS ON VIABILITY AND PROLIFERATION OF HUMAN RESISTANT CANCER CELLS --- p.24 / Chapter 2.1 --- Materials and Methods --- p.25 / Chapter 2.1.1 --- "Chemicals, Materials and Reagents" --- p.25 / Chapter 2.1.2 --- Methods --- p.26 / Chapter 2.1.2.1 --- Cell Lines and Cell Culture --- p.26 / Chapter 2.1.2.2 --- Preparation of POPs --- p.27 / Chapter 2.1.2.3 --- Sulforhodamine B assay --- p.27 / Chapter 2.1.2.4 --- Statistical analysis --- p.29 / Chapter 2.2 --- Results --- p.29 / Chapter 2.2.1 --- Effects of POPs on the viability of parental SW620 and P-gp-overexpressing resistant SW620/Ad300 cells --- p.29 / Chapter 2.2.2 --- Effects of POPs on the viability of parental MCF-7 and MRP1-overexpressing resistant MCF-7/VP cells --- p.33 / Chapter 2.2.3 --- Effects of POPs on the viability of parental MCF-7 and ABCG2-overexpressing resistant MCF-7/FLV1000 cells --- p.37 / Chapter 2.3 --- Discussion --- p.41 / Chapter 2.3.1 --- Structure activity relationship (SAR) --- p.43 / Chapter 2.3.2 --- Nine compounds relating to P-gp-mediated MDR --- p.46 / Chapter CHAPTER 3. --- MECHANISM OF NINE SELECTED POPS IN MODULATING P-GP-MEDIATED MDR --- p.49 / Chapter 3.1 --- Materials and Methods --- p.49 / Chapter 3.1.1 --- "Chemicals, Materials and Reagents" --- p.49 / Chapter 3.1.2 --- Methods --- p.53 / Chapter 3.1.2.1 --- Cell Lines and Cell Culture --- p.53 / Chapter 3.1.2.2 --- Extraction of nine POPs from M. tenacissima --- p.54 / Chapter 3.1.2.3 --- Sulforhodamine B (SRB) assay --- p.55 / Chapter 3.1.2.4 --- Flow cytometry assay --- p.55 / Chapter 3.1.2.5 --- P-gp ATPase assay --- p.56 / Chapter 3.1.2.6 --- Immuno-blot/Western blot analysis --- p.58 / Chapter 3.1.2.7 --- Reverse transcription and quantitative real-time PCR --- p.59 / Chapter 3.1.2.8 --- Statistical analysis --- p.60 / Chapter 3.2 --- Results --- p.60 / Chapter 3.2.1 --- Effects of nine selected POPs on the viability of sensitive human breast cancer MCF-7 cells --- p.60 / Chapter 3.2.2 --- Effects of nine selected POPs on the viability of MDR 1 -transfected HEK1 MDR1 cell line and its control vector transfected cell line HEK293 pcDNA3 --- p.61 / Chapter 3.2.3 --- Effects of nine selected POPs in inhibiting efflux of P-gp substrate --- p.64 / Chapter 3.2.4 --- Effects of nine selected POPs in modulating P-gp ATPase activity --- p.68 / Chapter 3.2.5 --- Effects of nine selected POPs in regulating P-gp protein expression --- p.69 / Chapter 3.2.6 --- MDR1 mRNA expression in various cell lines --- p.72 / Chapter 3.3 --- Discussion --- p.72 / Chapter 3.3.1 --- Effective POPs are targeting specifically P-gp overexpression --- p.73 / Chapter 3.3.2 --- Mechanistic understanding the circumvention of MDR by the effective POPs --- p.74 / Chapter 3.3.2.1 --- Relative potency for the reversal of P-gp-mediated MDR --- p.75 / Chapter 3.3.2.2 --- Inhibition of P-gp-mediated drug efflux across cell membrane by the effective POPs --- p.75 / Chapter 3.3.2.3 --- Stimulation of ATPase by the effective POPs --- p.76 / Chapter 3.3.2.4 --- No effect of POPs on the alteration of P-gp expression --- p.77 / Chapter 3.3.2.5 --- An overall summary of the mechanism of MDR reversal by the effective POPs --- p.78 / Chapter 3.3.3 --- Implication in drug disposition and drug-drug interactions --- p.79 / Chapter 3.3.4 --- Additional information for the structure activity relationship (SAR) --- p.80 / Chapter CHAPTER 4. --- EFFECTS OF CRUDE EXTRACT AND THREE MAJOR POLYOXYPREGNANES (POPS) OF MARS DEN I A TENACISSIMA --- p.81 / Chapter 4.1 --- Materials and Methods --- p.82 / Chapter 4.1.1 --- "Chemicals, Materials and Reagents" --- p.82 / Chapter 4.1.2 --- Methods --- p.82 / Chapter 4.1.2.1 --- "Preparation of M. tenacissima extract, artificial mixture and three fractions" --- p.82 / Chapter 4.1.2.2 --- Sulforhodamine B assay --- p.85 / Chapter 4.1.2.3 --- "Biotransformation study of POP68, POP69 and POP70" --- p.85 / Chapter 4.1.2.4 --- HPLC-MS analysis --- p.86 / Chapter 4.1.2.5 --- Animal care and housing conditions --- p.87 / Chapter 4.1.2.6 --- Toxicity studies of fraction 2 in mice --- p.88 / Chapter 4.1.2.7 --- Statistical analysis --- p.89 / Chapter 4.2 --- Results --- p.89 / Chapter 4.2.1 --- "Effects of crude extract, artificial mixture on the viability of sensitive human breast cancer MCF-7 cells" --- p.89 / Chapter 4.2.2 --- "Effects of crude extract, artificial mixture on the viability of sensitive SW620 and P-gp-overexpressing resistant SW620/Ad300 cells" --- p.90 / Chapter 4.2.3 --- "Metabolites of POP68, POP69 and POP70 after incubation with human intestinal microbiota" --- p.91 / Chapter 4.2.4 --- Toxicity of fraction 2 in mice --- p.94 / Chapter 4.3 --- Discussion --- p.98 / Chapter CHAPTER 5. --- FINAL DISCUSSION AND CONCLUSIONS --- p.105 / REFERENCES --- p.108

Identiferoai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_327404
Date January 2011
ContributorsChai, Stella., Chinese University of Hong Kong Graduate School. Division of Biomedical Sciences.
Source SetsThe Chinese University of Hong Kong
LanguageEnglish, Chinese
Detected LanguageEnglish
TypeText, bibliography
Formatprint, xxii, 126 leaves : ill. (some col.) ; 30 cm.
RightsUse of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/)

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