New synergistic combination therapy approaches with HDAC inhibitor quisinostat, cisplatin or PARP inhibitor talazoparib for urothelial carcinoma.

Autor: Meneceur S; Department of Urology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.; Center for Integrated Oncology (CIO) Düsseldorf, CIO Aachen Bonn Köln Düsseldorf, Düsseldorf, Germany., De Vos CE; Department of Urology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.; Center for Integrated Oncology (CIO) Düsseldorf, CIO Aachen Bonn Köln Düsseldorf, Düsseldorf, Germany., Petzsch P; Center for Integrated Oncology (CIO) Düsseldorf, CIO Aachen Bonn Köln Düsseldorf, Düsseldorf, Germany.; Genomics and Transcriptomics Laboratory (GTL), Biological and Medical Research Center (BMFZ), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Köhrer K; Center for Integrated Oncology (CIO) Düsseldorf, CIO Aachen Bonn Köln Düsseldorf, Düsseldorf, Germany.; Genomics and Transcriptomics Laboratory (GTL), Biological and Medical Research Center (BMFZ), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Niegisch G; Department of Urology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.; Center for Integrated Oncology (CIO) Düsseldorf, CIO Aachen Bonn Köln Düsseldorf, Düsseldorf, Germany., Hoffmann MJ; Department of Urology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.; Center for Integrated Oncology (CIO) Düsseldorf, CIO Aachen Bonn Köln Düsseldorf, Düsseldorf, Germany.
Jazyk: angličtina
Zdroj: Journal of cellular and molecular medicine [J Cell Mol Med] 2024 May; Vol. 28 (9), pp. e18342.
DOI: 10.1111/jcmm.18342
Abstrakt: Urothelial carcinoma (UC) urgently requires new therapeutic options. Histone deacetylases (HDAC) are frequently dysregulated in UC and constitute interesting targets for the development of alternative therapy options. Thus, we investigated the effect of the second generation HDAC inhibitor (HDACi) quisinostat in five UC cell lines (UCC) and two normal control cell lines in comparison to romidepsin, a well characterized HDACi which was previously shown to induce cell death and cell cycle arrest. In UCC, quisinostat led to cell cycle alterations, cell death induction and DNA damage, but was well tolerated by normal cells. Combinations of quisinostat with cisplatin or the PARP inhibitor talazoparib led to decrease in cell viability and significant synergistic effect in five UCCs and platinum-resistant sublines allowing dose reduction. Further analyses in UM-UC-3 and J82 at low dose ratio revealed that the mechanisms included cell cycle disturbance, apoptosis induction and DNA damage. These combinations appeared to be well tolerated in normal cells. In conclusion, our results suggest new promising combination regimes for treatment of UC, also in the cisplatin-resistant setting.
(© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz: