Dokument: Targeting mechanisms of the DNA damage response (DDR) to overcome acquired cisplatin resistance in tumor cells
| Titel: | Targeting mechanisms of the DNA damage response (DDR) to overcome acquired cisplatin resistance in tumor cells | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=69374 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20250423-125421-7 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Mann, Julia [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Fritz, Gerhard [Gutachter] Prof. Dr. Schmitt, Lutz [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Although cisplatin (CisPt) has been used as chemotherapeutic agent in the treatment of various cancer types for decades, acquired drug resistance of malignant cells remains a major clinical obstacle. Cisplatin’s primary mechanism of action is the induction of replicative stress by forming crosslinks in genomic DNA. This leads to activation of the DNA damage response (DDR), a complex network that regulates cell cycle arrest, DNA repair and cell death. Deregulations in these pathways may contribute to the development of CisPt resistance and their targeting is hypothesized to be a potential strategy to overcome acquired resistance to CisPt. Thus, we aimed to identify pharmacological DDR or DNA repair inhibitors that can re sensitize CisPt-resistant cells to CisPt treatment or, in combination with a second DDR inhibitor, circumvent acquired CisPt resistance.
To this end, CisPt resistant J82CisPt bladder cancer cells were treated with combinations of DDR /DNA repair inhibitors to identify additive or synergistic cytotoxic effects. To determine the universal significance of the findings, a selected combination treatment was tested for its cytotoxicity in CisPt resistant tumor cell lines originating from different tumor entities. We found that the combination of a CHK1 (PF477736) and a RAD51 inhibitor (B02) synergistically evoked cell death not only in J82CisPt, but also in cisplatin resistant A549CisPt lung cancer cells and SH-SY5YCisPt neuroblastoma cells. Investigations concerning the underlying molecular mechanisms of the synergism of B02 + PF477736 in J82CisPt suggest that the two inhibitors disrupt S-phase progression via replication fork stalling and excessive ssDNA formation. The inability to properly protect or restart the replication fork with inhibited RAD51 and CHK1 leads to replication fork collapse and ultimately cell death. Moreover, the cytotoxic effect of CHK1i + RAD51i was analyzed in non malignant human cells to make an initial assessment of possible adverse effects of the drug combination. Viability measurements revealed synergistic cytotoxicity of B02 + PF477736 in high proliferative human induced pluripotent stem cells, but rather additive effects in low proliferative Normal Human Dermal Fibroblasts. This finding underlines the assumption that highly replicative cell types are particularly affected by the co treatment, which targets the S-phase progression. Moreover, a xenograft model in mice was employed to assess the anticancer efficacy, as well as adverse effects of B02 and PF477736 in vivo. Due to poor tumor formation of the J82CisPt cells in vivo, the performed experiment did not provide unequivocal results on the antitumor efficacy of the treatment. At the same time, no adverse effects of the applied inhibitors were observed in the mice. In conclusion, this work could demonstrate that simultaneously inhibiting CHK1 and RAD51 as factors involved in the regulation of the replicative stress response is a promising approach to overcome acquired cisplatin resistance. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 23.04.2025 | |||||||
| Dateien geändert am: | 23.04.2025 | |||||||
| Promotionsantrag am: | 24.10.2024 | |||||||
| Datum der Promotion: | 19.03.2025 |
