Dokument: Promising Novel Therapeutic Strategies for Cisplatin Resistant Bladder Cancer
| Titel: | Promising Novel Therapeutic Strategies for Cisplatin Resistant Bladder Cancer | |||||||
| Weiterer Titel: | Neuartige Therapien Strategien für Cisplatin-resistenten Blasenkrebs | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=53150 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20200512-112836-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Wang, Chenyin [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Kassack, Matthias U. [Gutachter] Prof. Dr. Proksch, Peter [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 540 Chemie | |||||||
| Beschreibung: | Abstract
Bladder cancer is the most common malignancy of the urinary tract. Depending on the location of the tumors grown into the bladder, it can be divided into superficial and muscleinvasive bladder cancer. Although only 30% of patients have muscle-invasive bladder cancer as initial diagnosis, advanced disease occurs in another 15-30% of patients with a high grade of superficial carcinomas and leads to the development of life-threatening muscle-invasive tumors or metastatic disease. Platinum-based combination chemotherapy is the first-line treatment for advanced bladder cancer. However, the acquisition of cisplatin resistance has been frequently observed in cisplatin treated patients resulting in relapse. Furthermore, cancers including bladder cancer show aberrant epigenetics: increased promotor CpG island methylation and increased histone deacetylase (HDAC) expression both leading to transcriptional silencing, in particular of tumor suppressor and proapoptotic genes. Thus, the aim of this thesis was to establish a cellular model of cisplatin-resistant bladder cancer and to use this in vitro model for the discovery of novel therapeutic approaches against bladder cancer, in particular against chemoresistant cancer. Initially, the cisplatin-resistant bladder cancer cell line J82CisR was established from the sensitive cell line J82 by intermittent treatment with cisplatin. Following studies were then undertaken at the bladder cancer cell line J82, J82CisR, and RT-112. The first part of the thesis deals with combination treatments of the DNA methyltransferase inhibitor (DNMTi) decitabine and the class I HDAC inhibitor (HDACi) entinostat. Whereas decitabine and entinostat or combinations of the two could only partially reverse cisplatin resistance in J82CisR, the combination of decitabine and entinostat was highly synergistic in reducing the viability of bladder cancer cells by inducing cell cycle arrest and caspase 3/7- mediated apoptosis. Mechanistically, expression levels of the transcription factor FoxO1 were up-regulated in all three bladder cancer cell lines upon treatment with decitabine or entinostat or a combination of both. Furthermore, a significant increase in the expression of the proapoptotic protein Bim and the cell cycle regulator p21, both downstream targets of FoxO1, was observed upon epigenetic treatment. Importantly, the expression of Bim and p21 was reduced by addition of the FoxO1 inhibitor AS1842856 confirming the essential role of FoxO1 after epigenetic treatment. Abstract 2 In the second part of the thesis, nature-derived compounds were investigated for their cytotoxic potential in bladder cancer, particularly in chemoresistant cancers. The tetrahydroxanthone dimer phomoxanthone A (PXA) isolated from the endophytic fungus Phomopsis longicolla exhibited potent anti-cancer activity with low micromolar IC50 values in sensitive and cisplatin-resistant cell lines by caspase 3/7-mediated induction of apoptosis. Initially, PXA induces a fast depolarization of the mitochondrial membrane potential which may be due to degradation of the proton gradient along the inner mitochondrial membrane by acting as proton shuttle as computational studies suggest. A number of further natural products were investigated for their anticancer activity as e.g., two indole diterpenoids isolated from Zingiber officinale or a diketopiperazine isolated from a mangrove-derived endophytic fungus Penicillium brocae MA-231. These compounds showed potent cytotoxicity with sub-μM IC50 values. In conclusion, this thesis first, suggests the use of epigenetic modulation (DNMT- and HDAC-inhibitors) for the management of chemoresistant bladder cancer cells and second, has investigated nature-derived compounds with promising cytostatic activity, especially in resistant cancer cells, in particular phomoxanthone A targeting the mitochondrial potential. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische und Medizinische Chemie | |||||||
| Dokument erstellt am: | 12.05.2020 | |||||||
| Dateien geändert am: | 12.05.2020 | |||||||
| Promotionsantrag am: | 18.12.2019 | |||||||
| Datum der Promotion: | 18.12.2019 |
