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

• Published in: Journal of cellular and molecular medicine Vol. 28; no. 9; pp. e18342 - n/a
• Main Authors: Meneceur, Sarah, De Vos, Caroline E., Petzsch, Patrick, Köhrer, Karl, Niegisch, Günter, Hoffmann, Michèle J.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.05.2024; John Wiley and Sons Inc
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; Bladder cancer; Cancer therapies; Cell culture; Cell cycle; Cell Cycle - drug effects; Cell death; Cell Line, Tumor; Cell Survival - drug effects; Cell viability; Chemotherapy; Cisplatin; Cisplatin - pharmacology; DNA damage; DNA Damage - drug effects; Drug Synergism; Enzymes; Epigenetics; Fibroblasts; Flow cytometry; HDACi; Hematology; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Histones; Humans; Hydroxamic Acids - pharmacology; Hydroxamic Acids - therapeutic use; Immunoglobulins; Medical prognosis; Original; Phthalazines - pharmacology; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Proteins; quisinostat; Reagents; Regulation; Senescence; talazoparib; Targeted cancer therapy; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Urologic Neoplasms - drug therapy; Urologic Neoplasms - pathology; Urothelial carcinoma; quisinostat; cisplatin; talazoparib; HDACi; bladder cancer
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.18342

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.