Dokument: Investigation of Novel Combination Treatments with HDAC Inhibitors in Leukemia and Bladder Cancer Cell Lines
| Titel: | Investigation of Novel Combination Treatments with HDAC Inhibitors in Leukemia and Bladder Cancer Cell Lines |
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=73777 |
| URN (NBN): | urn:nbn:de:hbz:061-20260713-134645-5 |
| Kollektion: | Dissertationen |
| Sprache: | Englisch |
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation |
| Medientyp: | Text |
| Autor: | Bollmann, Lukas Michael [Autor] |
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| Beitragende: | Prof. Dr. Kassack, Matthias U. [Gutachter] Prof. Dr. Holger Gohlke [Gutachter] |
| Stichwörter: | HDAC, Epigenetics, bladder cancer, AML, cisplatin |
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 540 Chemie |
| Beschreibung: | Despite major advances in oncology, the 5-year survival rate for some cancers like acute myleoid leukemia (AML) or advanced muscle-invasive bladder cancer is low. Among the main reasons for the low survival rates in AML and bladder cancer are the heterogeneity, the chemoresistance and the epigenetic dysregulation of the cancer cells.
To face these problems and increase survival rates, combination treatments can be utilized. Combination treatments have several advantages, including targeting multiple targets and synergistic effects between the compounds, leading to a more potent and possibly more selective cytotoxic effect in the cancer cells. This thesis aimed to identify new combination partners targeting epigenetic dys-regulation for improved treatment of AML and muscle-invasive bladder cancer. Several AML cell lines and two pairs of native and cisplatin-resistant muscle-invasive bladder cancer cell lines were used. One important group of epigenetic regulators are histone deacetylases (HDACs), impacting a variety of intracellular processes. Dysregulation of HDACs in cells has emerged as a contributor to the development of cancer and chemoresistance. The HDAC family is classified into five distinct classes, comprising a total of 11 HDAC and 7 sirtuin enzymes. The use of selective histone deacetylase inhibitors (HDACi) should enable more targeted and efficent therapy than the use of broad-spectrum HDACi. The first part of the thesis focuses on AML. Herein, the new class IIa specific HDACi YAK540 was intensively characterized. Subsequently, YAK540 in combination with the proteasome inhibitor (PI) bortezomib (BTZ) was analyzed in the AML cell lines THP-1, HL-60, and MONO-MAC-6 as well as in the chronic myeloid leukemia cell line K562. BTZ is used clinically for the treatment of multiple myeloma and is currently in clinical trials for the treatment of AML. The first study showed that the combination of the novel class IIa specific HDACi YAK540 with BTZ induced a synergistic cytotoxic effect with increased expression of p21 and enhanced caspase 3/7-mediated apoptosis. In a follow-up study, FFK24, a more potent class IIa HDACi was characterized and evaluated in combination with BTZ in the AML cell line THP-1, again demonstrating increased expression of p21 and a synergistic cytotoxic effect. The second part of the thesis addresses the problem of cisplatin resistance in bladder cancer. The triple combination of the class I HDACi entinostat, a bromodomain and extra-terminal motif inhibitor (BETi; JQ1, OTX015) and cisplatin was investigated in two pairs of sensitive and cisplatin-resistant muscle-invasive bladder cancer cell lines (J82, J82 cisR and T24, T24 LTT). In addition, the dual inhibitor compound 20, (a combined HDAC- and BET-inhibitor) was investigated in combination with cisplatin. Entinostat plus JQ1 or OTX015 as well as compound 20 showed complete (J82 cisR) or partial (T24 LTT) reversal of cisplatin resistance. The combinations were highly synergistic and resulted in increased caspase-mediated apoptosis most likely triggered by enhanced expression of p21, Bim, and FOXO1. In conclusion, HDACi are promising combination partners for different drug classes, such as PI, BETi and cisplatin. These combinations could contribute to the development of new therapeutic options for AML or bladder cancer, including overcoming chemoresistance. |
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz |
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische und Medizinische Chemie |
| Dokument erstellt am: | 13.07.2026 |
| Dateien geändert am: | 13.07.2026 |
| Promotionsantrag am: | 22.01.2026 |
| Datum der Promotion: | 10.06.2026 |
