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 (compound20) 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 compound20. 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.
背景/目的。顺铂是晚期尿路上皮癌一线治疗方案的重要组成部分。顺铂耐药性是一个主要问题，但可通过联合治疗（如表观遗传异常靶向治疗）来克服。本研究探讨了I类HDAC抑制剂恩替诺特和溴结构域抑制剂（BETis）对两对敏感型和顺铂耐药型膀胱癌细胞系中顺铂效价的影响。与原始细胞系J82和T24相比，顺铂耐药细胞系J82cisR和T24 LTT对顺铂的耐药性分别提高了3.8倍和24倍。此外，研究还考察了一种兼具HDAC抑制剂和BET抑制剂结构特征的杂合化合物（化合物20）。结果。我们发现恩替诺特、JQ1与顺铂联用可完全（J82cisR）或部分（T24 LTT）逆转化疗耐药性。正在进行临床试验的BET抑制剂JQ35、OTX015以及化合物20也表现出相同效果。这些联合方案具有高度协同作用（Chou Talalay分析），能通过增强p21、Bim和FOXO1表达来促进caspase介导的细胞凋亡。值得注意的是，这些联合方案对非癌细胞系HBLAK和HEK293的毒性至少降低4倍。结论。恩替诺特、BET抑制剂与顺铂的三联疗法具有高度协同效应，能逆转顺铂耐药性，可能成为膀胱癌的新型治疗策略。
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