溴结构域抑制剂恩替诺特与顺铂的三联组合是一种有前景的膀胱癌治疗方案。

Triple Combination of Entinostat, a Bromodomain Inhibitor, and Cisplatin Is a Promising Treatment Option for Bladder Cancer.

作者信息

Bollmann Lukas M, Lange Friedrich, Hamacher Alexandra, Biermann Lukas, Schäker-Hübner Linda, Hansen Finn K, Kassack Matthias U

机构信息

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.

Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

出版信息

Cancers (Basel). 2024 Oct 2;16(19):3374. doi: 10.3390/cancers16193374.

DOI:10.3390/cancers16193374

PMID:39409994

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11476342/

Abstract

BACKGROUND/OBJECTIVES: Cisplatin is part of the first-line treatment of advanced urothelial carcinoma. Cisplatin resistance is a major problem but may be overcome by combination treatments such as targeting epigenetic aberrances. Here, we investigated the effect of the class I HDACi entinostat and bromodomain inhibitors (BETis) on the potency of cisplatin in two pairs of sensitive and cisplatin-resistant bladder cancer cell lines. Cisplatin-resistant J82cisR and T24 LTT were 3.8- and 24-fold more resistant to cisplatin compared to the native cell lines J82 and T24. In addition, a hybrid compound (compound ) comprising structural features of an HDACi and a BETi was investigated.

RESULTS

We found complete (J82cisR) or partial (T24 LTT) reversal of chemoresistance upon combination of entinostat, JQ1, and cisplatin. The same was found for the BETis JQ35 and OTX015, both in clinical trials, and for compound . The combinations were highly synergistic (Chou Talalay analysis) and increased caspase-mediated apoptosis accompanied by enhanced expression of p21, Bim, and FOXO1. Notably, the combinations were at least 4-fold less toxic in non-cancer cell lines HBLAK and HEK293.

CONCLUSIONS

The triple combination of entinostat, a BETi, and cisplatin is highly synergistic, reverses cisplatin resistance, and may thus serve as a novel therapeutic approach for bladder cancer.

摘要

背景/目的：顺铂是晚期尿路上皮癌一线治疗方案的一部分。顺铂耐药是一个主要问题，但可通过靶向表观遗传异常等联合治疗来克服。在此，我们研究了I类组蛋白去乙酰化酶抑制剂（HDACi）恩替诺特和溴结构域抑制剂（BETi）对两对敏感和顺铂耐药膀胱癌细胞系中顺铂效力的影响。与亲本细胞系J82和T24相比，顺铂耐药的J82cisR和T24 LTT对顺铂的耐药性分别高3.8倍和24倍。此外，还研究了一种包含HDACi和BETi结构特征的杂合化合物（化合物）。

结果

我们发现恩替诺特、JQ1与顺铂联合使用时，化疗耐药性完全（J82cisR）或部分（T24 LTT）逆转。在临床试验中的BETi JQ35和OTX015以及化合物也有同样的发现。这些联合用药具有高度协同性（Chou Talalay分析），并增加了半胱天冬酶介导的细胞凋亡，同时伴有p21、Bim和FOXO1表达增强。值得注意的是，这些联合用药在非癌细胞系HBLAK和HEK293中的毒性至少低4倍。