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.
J Cell Mol Med. 2024 May;28(9):e18342. 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.
迫切需要为尿路上皮癌（UC）提供新的治疗选择。组蛋白去乙酰化酶（HDAC）在 UC 中经常失调，是开发替代治疗选择的有趣靶点。因此，我们研究了第二代 HDAC 抑制剂（HDACi）quinostat 在五种 UC 细胞系（UCC）和两种正常对照细胞系中的作用，与先前显示可诱导细胞死亡和细胞周期停滞的罗米地辛（一种特征良好的 HDACi）进行了比较。在 UCC 中，quinostat 导致细胞周期改变、细胞死亡诱导和 DNA 损伤，但对正常细胞具有良好的耐受性。quinostat 与顺铂或 PARP 抑制剂 talazoparib 的组合导致五种 UCC 和铂耐药亚系的细胞活力降低，并产生显著的协同作用，从而允许减少剂量。在低剂量比的 UM-UC-3 和 J82 中的进一步分析表明，这些机制包括细胞周期紊乱、细胞凋亡诱导和 DNA 损伤。这些组合在正常细胞中似乎具有良好的耐受性。总之，我们的研究结果表明，对于 UC 的治疗，包括在铂耐药环境中，存在新的有前途的联合治疗方案。
