Yes / When the 'CO-releasing molecule-3', CORM-3 (Ru(CO)3Cl(glycinate)), is dissolved in water it forms a range of ruthenium complexes. These are taken up by cells and bind to intracellular ligands, notably thiols such as cysteine and glutathione, where the Ru(II) reaches high intracellular concentrations. Here, we show that the Ru(II) ion also binds to DNA, at exposed guanosine N7 positions. It therefore has a similar cellular target to the anticancer drug cisplatin, but not identical, because Ru(II) shows no evidence of forming intramolecular crossbridges in the DNA. The reaction is slow, and with excess Ru, intermolecular DNA crossbridges are formed. The addition of CORM-3 to human colorectal cancer cells leads to strand breaks in the DNA, as assessed by the alkaline comet assay. DNA damage is inhibited by growth media containing amino acids, which bind to extracellular Ru and prevent its entry into cells. We conclude that the cytotoxicity of Ru(II) is different from that of platinum, making it a promising development target for cancer therapeutics.

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by Chung Lung Ying. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves 149-157). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abbreviations --- p.ii / Abstracts --- p.v / List of figures --- p.ix / List of tables --- p.xii / Contents --- p.xiii / Contents / General Introduction --- p.1 / Chapter CHAPTER ONE --- CISPLATIN RESISTANCE MECHANISMS / Chapter 1.1 --- INTRODUCTION --- p.3 / Chapter 1.1.1 --- History of Cisplatin as An Anticancer Drug --- p.3 / Chapter 1.1.2 --- Active Mechanisms of Cisplatin --- p.8 / Chapter 1.1.3 --- Formation of DNA Adducts --- p.8 / Chapter 1.1.4 --- Cisplatin Resistance Mechanisms --- p.9 / Chapter 1.1.4.1 --- Intracellular Accumulation of Cisplatin --- p.11 / Chapter 1.1.4.2 --- Glutathione-S-transferase and Glutathion --- p.12 / Chapter 1.1.4.3 --- Metallothionein --- p.16 / Chapter 1.1.4.4 --- Cell Cycle Perturbation --- p.16 / Chapter 1.1.4.5 --- P-glycoprotein --- p.17 / Chapter 1.1.4.6 --- Multidrug Resistant Protein --- p.19 / Chapter 1.1.4.7 --- Topoisomerase II --- p.20 / Chapter 1.1.4.8 --- DNA Repair --- p.22 / Chapter 1.1.4.9 --- Induction of Programme Cell Death --- p.23 / Chapter 1.2 --- OBJECTIVES --- p.27 / Chapter 1.3 --- MATERIALS AND METHODS / Chapter 1.3.1 --- Materials --- p.28 / Chapter 1.3.2 --- Methods --- p.31 / Chapter 1.3.2.1 --- Cell Lines --- p.31 / Chapter 1.3.2.2 --- Drug Sensitivity Assay --- p.31 / Chapter 1.3.2.3 --- Platinum Uptake --- p.32 / Chapter 1.3.2.4 --- Cell Cycle Analysis --- p.32 / Chapter 1.3.2.5 --- Western Blot Analysis --- p.33 / Chapter 1.3.2.6 --- Glutathione Content Determination --- p.36 / Chapter 1.3.2.7 --- DNA Fragmentation --- p.36 / Chapter 1.3.2.8 --- JC-1 Staining --- p.37 / Chapter 1.3.2.9 --- HE and DCF Staining --- p.38 / Chapter 1.3.2.10 --- Quantitative RT-PCR --- p.38 / Chapter 1.4 --- RESULTS / Chapter 1.4.1 --- Cisplatin Sensitivity of A431 Cells by MTT Assay --- p.40 / Chapter 1.4.2 --- Cross-resistance to Anti-cancer Drugs --- p.40 / Chapter 1.4.3 --- Quantitation of Cisplatin Accumulation in A431 Cells by AAS --- p.44 / Chapter 1.4.4 --- Drug Detoxification Agent --- p.45 / Chapter 1.4.5 --- Detection of Cell Cycle Arrest by Flow Cytometer --- p.47 / Chapter 1.4.6 --- Expression of Drug Resistance Related Genes --- p.48 / Chapter 1.4.7 --- Detection of Apoptosis by DNA Fragmentation --- p.50 / Chapter 1.4.8 --- Role of Mitochondria and Reactive Oxygen Species by Flow Cytometer --- p.52 / Chapter 1.4.9 --- Detection of Apoptotic mRNA Level by Quantitative RT-PCR --- p.57 / Chapter 1.4.10 --- Detection of Apoptotic Protein Level by Western Blot Analysis --- p.57 / Chapter 1.5 --- DISCUSSIONS --- p.59 / Chapter CHAPTER TWO: --- THE INTERACTION BETWEEN DRUG RESISTANCE MECHANISMS AND GROWTH FACTOR SIGNALLING PATHWAY / Chapter 2.1 --- INTRODUCTION --- p.63 / Chapter 2.1.1 --- Structure of EGF and EGFR --- p.64 / Chapter 2.1.2 --- Growth Factor Signal Transduction Pathway --- p.69 / Chapter 2.1.3 --- Biological Effect of EGF --- p.69 / Chapter 2.1.3.1 --- Modification of Drug Sensitivity by EGF --- p.71 / Chapter 2.2 --- OBJECTIVES --- p.74 / Chapter 2.3 --- MATERIALS AND METHODS / Chapter 2.3.1 --- Materials --- p.75 / Chapter 2.3.2 --- Methods / Chapter 2.3.2.1 --- Cell Lines --- p.76 / Chapter 2.3.2.2 --- Drug Sensitivity Assay --- p.77 / Chapter 2.3.2.3 --- Northern Blot Analysis --- p.77 / Chapter 2.3.2.4 --- Southern Blot Analysis --- p.78 / Chapter 2.3.2.5 --- Others --- p.78 / Chapter 2.4 --- RESULTS / Chapter 2.4.1 --- Sensitivity to EGF --- p.79 / Chapter 2.4.2 --- EGFR Expression Levels --- p.80 / Chapter 2.4.3 --- EGF Induced Protein Phosphorylation Pattern --- p.84 / Chapter 2.4.4 --- Effect of EGF on A431 Cells --- p.86 / Chapter 2.4.5 --- Response of Cells to Agents Targeting on EGF Signalling Pathway --- p.91 / Chapter 2.4.6 --- Response of Cells to Other Growth Factors --- p.97 / Chapter 2.4.7 --- Sensitivity of Cells to Different Anti-cancer Drugs --- p.99 / Chapter 2.4.8 --- Drug Resistance Mechanisms --- p.103 / Chapter 2.4.9 --- 5-Fluorouracil Sensitivity in A431 Cells --- p.108 / Chapter 2.4.10 --- Cisplatin Sensitivity in A431 Cells --- p.113 / Chapter 2.5 --- DISCUSSIONS --- p.117 / Chapter CHAPTER THREE: --- IDENTIFICATION OF DIFFERENTIALLY EXPRESSED GENE IN A431 CELLS BY DIFFERENTIAL DISPLAY / Chapter 3.1 --- INTRODUCTION --- p.122 / Chapter 3.2 --- MATERIALS AND METHODS / Chapter 3.2.1 --- Materials --- p.128 / Chapter 3.2.2 --- Methods / Chapter 3.2.2.1 --- Identification of Differentially Expressed Genes by RT-PCR / Chapter 3.2.2.2 --- Cloning of a Differentially Expressed cDNAs --- p.129 / Chapter 3.2.2.3 --- Screening and Sequencing of cDNA Inserts --- p.130 / Chapter 3.2.2.4 --- Rapid Amplification of cDNA Ends (RACE) --- p.131 / Chapter 3.2.2.5 --- Amplifcation Reaction --- p.131 / Chapter 3.2.2.6 --- Cloning and Sequencing of the RACE Fragment --- p.132 / Chapter 3.3 --- RESULTS / Chapter 3.3.1 --- Identification of novel cDNA by mRNA differential display --- p.133 / Chapter 3.4 --- DISCUSSIONS --- p.145 / General Conclusion --- p.147 / References --- p.149

Gao, Si. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 77-85). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.ii / Abstract (in Chinese) --- p.iv / List of Abbreviations --- p.v / List of Figures --- p.vii / Table of Contents --- p.ix / Chapter Chapter One: --- Introduction --- p.1 / Chapter 1.1. --- Cancer --- p.1 / Chapter 1.2. --- Chemotherapy --- p.2 / Chapter 1.3. --- Cisplatin --- p.3 / Chapter 1.4. --- Cisplatin-induced nephrotoxicity --- p.4 / Chapter 1.5. --- Mechanisms of cisplatin-induced nephrotoxicity --- p.5 / Chapter 1.5.1. --- Apoptosis in cisplatin-induced nephrotoxicity --- p.5 / Chapter 1.5.2. --- MAPK activation in cisplatin-induced nephrotoxicity --- p.7 / Chapter 1.5.3. --- Oxidative stress in cisplatin-induced nephrotoxicity --- p.8 / Chapter 1.6. --- Polyphenols --- p.10 / Chapter 1.7. --- Anthocyanins --- p.10 / Chapter 1.8. --- Rose --- p.11 / Chapter 1.9. --- Cyanidin --- p.12 / Chapter 1.10. --- Objectives of this project --- p.13 / Chapter Chapter Two: --- Materials and Methods --- p.15 / Chapter 2.1. --- Materials --- p.15 / Chapter 2.2. --- Cell culture --- p.15 / Chapter 2.3. --- Drug treatment --- p.16 / Chapter 2.4. --- MTT assay --- p.16 / Chapter 2.5. --- Lactate dehydrogenase (LDH) assay --- p.16 / Chapter 2.6. --- TUNEL assay and DAPI staining --- p.17 / Chapter 2.7. --- Flow cytometric analysis --- p.17 / Chapter 2.8. --- Determination of caspase-3 activity --- p.18 / Chapter 2.9. --- Measurement of ROS generation --- p.18 / Chapter 2.10. --- Evaluation of mitochondrial membrane potential --- p.19 / Chapter 2.11. --- Single Cell Gel Electrophoresis (Comet Assay) --- p.19 / Chapter 2.12. --- Western blot analysis --- p.20 / Chapter 2.13. --- Statistical analysis --- p.21 / Chapter Chapter Three: --- Results --- p.22 / Chapter 3.1. --- Cyanidin attenuates cisplatin-induced cytotoxicity in HK-2 cells --- p.22 / Chapter 3.1.1. --- Cytotoxicity induces by cisplatin in HK-2 cells --- p.22 / Chapter 3.1.2. --- Rose extract attenuates cisplatin-induced cytotoxicity and LDH leakage --- p.26 / Chapter 3.1.3. --- Cyanidin attenuates cisplatin-induced cytotoxicity and LDH leakage --- p.26 / Chapter 3.1.4. --- Cyanidin did not affect cisplatin-induced cytotoxicity in Hela cell --- p.30 / Chapter 3.2. --- Cyanidin rescues HK-2 cells from cisplatin-induced apoptosis --- p.31 / Chapter 3.2.1. --- Cisplatin induces cell apoptosis in HK-2 cells --- p.31 / Chapter 3.2.2. --- Rose extract rescues HK-2 cells from cisplatin-induced apoptosis --- p.31 / Chapter 3.2.3. --- Cyanidin rescues HK-2 cells from cisplatin-induced apoptosis --- p.32 / Chapter 3.3. --- Cyanidin suppresses cisplatin-induced activation of caspase and cleavage of PARP --- p.38 / Chapter 3.3.1. --- Cisplatin induces activation of caspase-3 --- p.38 / Chapter 3.3.2. --- Rose extract suppresses cisplatin-induced activation of caspase-3 --- p.38 / Chapter 3.3.3. --- Cyanidin suppresses cisplatin-induced activation of caspase-3 --- p.38 / Chapter 3.3.4. --- Rose extract suppresses cisplatin-induced caspase activation and PARP cleavage --- p.41 / Chapter 3.3.5. --- Cyanidin suppresses cisplatin-induced caspase activation and PARP cleavage --- p.43 / Chapter 3.4. --- Cyanidin rescues HK-2 cells from cisplatin-induced mitochondrial dysfuntion by regulating the expression of Bcl-2 family proteins --- p.43 / Chapter 3.4.1. --- Cyanidin prevents cisplatin-induced loss of mitochondrial membrane potential (A^m) --- p.43 / Chapter 3.4.2. --- Cyanidin regulates the expression of Bcl-2 family proteins to prevent cisplatin-induced mitochondrial dysfunction --- p.44 / Chapter 3.5. --- Cyanidin reduces cisplatin-induced apoptosis by suppressing the activation of p53 --- p.46 / Chapter 3.6. --- Cyanidin inhibits ROS-mediated DNA damage in HK-2 cells --- p.48 / Chapter 3.6.1. --- Cyanidin prevents cisplatin-induced DNA damage --- p.48 / Chapter 3.6.2. --- Cyanidin inhibits cisplatin-induced accumulation of ROS --- p.48 / Chapter 3.7. --- "Cyanidin suppresses cisplatin-induced apoptosis by activation of AKT, JNK and ERK" --- p.52 / Chapter 3.7.1. --- Cisplatin activates ERK and AKT pathways --- p.52 / Chapter 3.7.2. --- Cyanidin suppresses cisplatin-induced activation of MAPKs and AKT pathways --- p.52 / Chapter 3.7.3. --- AKT and ERK Inhibitors attenuates cisplatin-induced apoptosis in HK-2 cells --- p.53 / Chapter Chapter Four: --- Discussion --- p.60 / Chapter 4.1. --- Cell model and cisplatin treatment --- p.60 / Chapter 4.2. --- Cisplatin nephrotoxicity and its renoprevention --- p.61 / Chapter 4.3. --- Rose extract prevents cisplatin-induced apoptosis in HK-2 cells --- p.62 / Chapter 4.3.1. --- Rose extract prevents cisplatin-induced apoptosis in HK-2 cells --- p.63 / Chapter 4.3.2. --- Rose extract inhibits cisplatin-induced caspase activation and PARP cleavage --- p.64 / Chapter 4.4. --- Cyanidin prevents cisplatin-induced apoptosis in HK-2 cells --- p.66 / Chapter 4.4.1. --- Cyanidin will not affect cisplatin-induced cell death in HeLa cells --- p.66 / Chapter 4.4.2. --- Cyanidin prevents cisplatin-induced apoptosis by inhibiting caspase activation and PARP cleavage in HK-2 cells --- p.66 / Chapter 4.4.3. --- Cyanidin prevents the cisplatin-induced loss of mitochondrial membrane potential by regulating Bcl-2 proteins in HK-2 cells --- p.67 / Chapter 4.4.4. --- Cyanidin suppresses cisplatin-induced total and phosphorylated p53 activation --- p.68 / Chapter 4.4.5. --- Cyanidin prevents the cisplatin-induced overproduction of intracellular ROS and subsequent DNA damage in HK-2 cells --- p.69 / Chapter 4.4.6. --- Cyanidin suppresses the cisplatin-induced activation of MAPKs and AKT pathways in HK-2 cells --- p.71 / Chapter Chapter Five: --- Conclusion --- p.74 / References --- p.77

Das Ovarialkarzinom ist eine maligne Entartung der Eierstöcke und die achthäufigste Krebserkrankung in Deutschland. Aufgrund einer initialen langen symptomfreien Zeit und einer raschen Dynamik wird die Erkrankung meist erst im fortgeschrittenen Stadium, d.h. im Stadium III oder IV diagnostiziert, welches mit einer geringen 5-Jahres-Überlebenswahrscheinlichkeit von ca. 43 % einhergeht. Aktuell beruht die Standard-therapie auf einer radikalen Operation mit dem Ziel der makroskopischen Komplettresektion gefolgt von einer Platin/Paclitaxel-basierten Chemotherapie, welche im fortgeschrittenen Stadium mit dem Antikörper Bevacizumab kombiniert wird. Doch bis zu 85 % der Patientinnen mit fortgeschrittenem Ovarialkarzinom erleiden ein Rezidiv, und dabei stellt vor allem die Platin-Resistenz ein großes Problem dar. Im Rahmen dieser Arbeit wurde die Wirkung des zugelassenen H1-Antihistaminikums Diphenhydramin (DIPH) auf die platin-basierte Chemotherapie in Ovarialkarzinomzellen in vitro und in vivo untersucht. Während frühere Arbeiten eher eine schützende Wirkung von DIPH vor den Nebenwirkungen (z.B. Nephrotoxizität, Ototoxizität) der Platin-Therapie berichtet haben, wird in dieser Arbeit gezeigt, dass DIPH außerdem überraschenderweise in platin-resistenten Ovarialkarzinomzellen als „Platin-Sensitizer“ fungieren kann, da in der Kombinationstherapie Cisplatin mit DIPH eine Erhöhung der intrazellulären DNA-Platinierung, sowie der Apoptoseinduktion beobachtet wurde. Nachfolgende Experimente belegen, dass DIPH, neben seiner bekannten Funktion als H1-Antagonist, die Transportkapazitäten der Effluxpumpen MRP2, MRP3 und MRP5 inhibiert, welche bereits mit der Platin-Resistenz im Ovarialkarzinom in Verbindung gebracht wurden. Diese Erkenntnis unterstützt die Hypothese, dass DIPH Tumorzellen für die Cisplatin-Behandlung sensitiviert, indem der MRP-vermittelte Cisplatin-Efflux inhibiert wird. Darüber hinaus wurde in dieser Arbeit erfolgreich ein intraperitoneales Mausmodell für das platin-resistente Ovarialkarzinom mit Hilfe von Biolumineszenzimaging etabliert, um den Effekt von DIPH als möglichen „Platin-Sensitizer“ auch in vivo zu untersuchen. Es zeigte sich, dass mit Cisplatin und DIPH behandelte Versuchstiere tendenziell ein geringeres intraperitoneales Tumorwachstum aufwiesen als die mit Cisplatin behandelten Versuchstiere, was für eine mögliche Rolle von DIPH als Platin-Sensitizer spricht. Jedoch konnte eine statistische Signifikanz dieses Effektes auf Grund einiger technischer Limitationen des etablierten Mausmodells bislang noch nicht gezeigt werden. Ziel der vorliegenden Arbeit ist es, den Effekt von DIPH auf die platin-basierte Chemotherapie in einem umfassenden experimentellen in vitro Ansatz zu erforschen. In diesem Kontext wurde eine pharmakologische Strategie zur DIPH-vermittelten Sensitivierung des platin-resistenten Ovarialkarzinoms entwickelt, die anschließend in einem in vivo System präliminär getestet wurde. Die Ergebnisse liefern insgesamt eine vielversprechende Basis für weiterführende präklinische in vivo Versuche mit DIPH im Rahmen eines „Drug repositioning“ Ansatzes. / Ovarian cancer is a malignancy of the ovaries and the eighth most common cancer in Germany. Due to an initial long symptom-free period and rapid dynamics, the disease is usually diagnosed only at an advanced stage, i.e. stage III or IV, which is associated with a low 5-year survival probability of about 43 %. Currently, standard therapy is based on radical surgery with the goal of complete macroscopic resection followed by platinum/paclitaxel-based chemotherapy, which is combined with the antibody bevacizumab in advanced stages. However, up to 85 % of patients with advanced ovarian cancer experience recurrence, and platinum resistance in particular is a major problem. In this dissertation, the effect of the approved H1 antihistamine diphenhydramine (DIPH) on platinum-based chemotherapy was investigated in ovarian cancer cells in vitro and in vivo. While previous work has tended to report a protective effect of DIPH against the side effects (e.g., nephrotoxicity, ototoxicity) of platinum therapy, this work demonstrates that DIPH can also, surprisingly, act as a 'platinum sensitizer' in platinum-resistant ovarian cancer cells, as an increase in intracellular DNA platinization, as well as apoptosis induction, was observed in combination therapy with cisplatin and DIPH. Subsequent experiments indicate that DIPH, in addition to its known function as an H1 antagonist, inhibits the transport capacities of the efflux pumps MRP2, MRP3, and MRP5, which have previously been associated to platinum resistance in ovarian cancer. This finding supports the hypothesis that DIPH sensitizes tumor cells to cisplatin treatment by inhibiting MRP-mediated cisplatin efflux. In addition, this work successfully established an intraperitoneal mouse model for platinum-resistant ovarian cancer using bioluminescence imaging to investigate the effect of DIPH as a potential 'platinum sensitizer' in vivo as well. It was found that experimental animals treated with cisplatin and DIPH tended to have lower intraperitoneal tumor growth than those treated with cisplatin, suggesting a possible role of DIPH as a platinum sensitizer. However, statistical significance of this effect has not yet been demonstrated due to some technical limitations of the established mouse model. The aim of the present work is to explore the effect of DIPH on platinum-based chemotherapy in a comprehensive experimental in vitro approach. In this context, a pharmacological strategy for DIPH-mediated sensitization of platinum-resistant ovarian cancer was developed and subsequently preliminarily tested in an in vivo system. Overall, the results provide a promising basis for further preclinical in vivo trials with DIPH in the context of a 'drug repositioning' approach.

Pang Siu Kwong. / "August 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (p. 181-191) / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Plusieurs évidences suggèrent que des membres impliqués dans le contrôle de l'activation de la cascade apoptotique et particulièrement les membres de la famille de protéines Bcl-2 pourraient jouer un rôle dans le phénomène de résistance observé dans les tumeurs ovariennes. Le but de cette étude est de déterminer l'importance relative de la protéine Bcl-2 dans le phénomène de résistance clinique à la chimiothérapie dans le cancer ovarien, plus précisément au cisplatin. L'analyse de l'expression de la protéine Bcl-2 dans des cellules d'ovaire normales et cancéreuses a démontré une surexpression de la protéine dans les cellules cancéreuses par rapport aux cellules d'ovaire normales, mais aucune corrélation entre l'expression de la protéine Bcl-2 et la sensibilité au cisplatin des cellules d'ovaire cancéreuses n'a pu être établie. Pour pouvoir mieux évaluer le rôle de la protéine Bcl-2 dans le phénomène de résistance, nous avons utilisé un anticorps monovalent modifié (scFv) dirigé contre cette dernière. Ce scFv agit essentiellement comme un inhibiteur spécifique de la protéine Bcl-2 ans les cellules.

Background Cisplatin is used for treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC) but treatment with cisplatin often leads to acquired resistance to cisplatin, resulting in poor patient survival. Globotriaosylceramide (Gb3) and multidrug resistance protein 1 (MDR1) have been associated with cisplatin resistance. Gb3 serves as a receptor for verotoxin-1 (VT-1), which induces apoptosis, and has been shown to have a functional dependency to MDR1 and heat shock protein 70 (HSP7o). The Bcl-2 family of proteins and inhibitors of apoptosis (IAPs) are key regulators of apoptosis. BH3-mimetics mimic pro-apoptotic BH3-only proteins, while Smac mimetics mimic the IAP-binding protein Smac/Diablo. These drugs have shown great promise in reversing cisplatin resistance. Exosomes are small bio-nanoparticles secreted and taken up by both cancer cells and normal cells. They have the ability to transfer properties between cells and have been shown to confer resistance to cisplatin. Methods In this thesis, NSCLC cell line H1299 and MPM cell line P31 were studied using western blot, flow cytometry, proteome profilers, confocal microscopy and gene expression arrays to investigate changes in protein and gene expression after acquisition of cisplatin resistance (P31res and H1299res) or after incubation with exosomes or drugs that target these. The cytotoxic and apoptotic effects were studied using fluorometric cytotoxicity assay (FMCA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results This thesis confirms that Gb3 is a potential target for cisplatin resistance reversal. Incubation with glycosphingolipid production inhibitor DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) and VT-1 led to reduced Gb3 cell surface expression and increased cytotoxic effect of cisplatin in all cell lines. Gb3 and MDR1 was not co-localized in any studied cell line, but Gb3 and HSP70 were co-localized on the cell surface and PPMP and VT-1 led to a decrease of both Gb3 and HSP70. Both BH3-mimetic obatoclax and Smac mimetic AT-406 had an additive effect on cisplatin-induced cytotoxicity and apoptosis in P31 and a synergistic effect in P31res. Results indicate that exosomes from cisplatin-resistant cell lines can transfer HSP70 to the surface of cells. Conclusion Cell surface Gb3 and HSP70, the Bcl-2/IAP-family proteins and exosomal transfer of cisplatin resistance characteristics are potential targets in combatting cisplatin resistance that show therapeutic promise and warrant further research.

published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy