Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling
Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling
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新型混合分子通过抑制 JAK1-STAT3-BCL2 信号传导克服实体瘤对 HDAC 抑制剂的有限反应
DOI：
10.7150/thno.26627
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发表时间：
2018-01-01
期刊：
影响因子：
12.4
通讯作者：
Xiang, Rong
中科院分区：
文献类型：
--
作者：
Huang, Zhi;Zhou, Wei;Xiang, Rong
尽管在临床前模型中取得了初步进展，但大多数已知的作为单一药物使用的组蛋白去乙酰化酶抑制剂（HDACi），在几乎所有类型的实体瘤中均未显示出临床益处。因此，HDACi在实体瘤中的疗效仍不确定。在此，我们研发出一种混合型HDAC抑制剂，可使实体瘤对HDAC靶向治疗更为敏感。
方法：设计并合成了一种具有新颖结构的杂合分子Roxyl - zhc - 84。分析了Roxyl - zhc - 84的药代动力学和毒性。通过在体外评估细胞生长、凋亡和细胞周期，并在三种体内小鼠模型中进行研究，探究Roxyl - zhc - 84对实体瘤的抗肿瘤作用，并与相应的对照抑制剂单独使用或联合使用的效果进行比较。进行基因集富集分析，并在体外和体内的机制研究中确定相关的JAK1 - STAT3 - BCL2信号通路。
结果：Roxyl - zhc - 84显示出良好的药代动力学特性和低毒性。新型杂合抑制剂Roxyl - zhc - 84可诱导乳腺癌和卵巢癌细胞系发生细胞凋亡和G1期阻滞。在三种小鼠模型中，口服Roxyl - zhc - 84可导致肿瘤显著消退，且无明显毒性。此外，Roxyl - zhc - 84通过克服JAK1 - STAT3 - BCL2介导的耐药性，显著改善了传统HDAC抑制剂在实体瘤中有限的疗效。无论是在体外还是体内，Roxyl - zhc - 84治疗的疗效都远远优于HDAC和JAK1抑制剂联合使用的效果。
结论：使用Roxyl - zhc - 84同时抑制HDAC和CDK，并额外靶向JAK1，通过克服JAK1 - STAT3 - BCL2介导的耐药性，解决了传统HDAC抑制剂在实体瘤中疗效有限的问题，为使实体瘤对HDACi治疗敏感提供了一种合理的多靶点治疗方法。
Despite initial progress in preclinical models, most known histone deacetylase inhibitors (HDACis) used as a single agent have failed to show clinical benefits in nearly all types of solid tumours. Hence, the efficacy of HDACis in solid tumours remains uncertain. Herein, we developed a hybrid HDAC inhibitor that sensitized solid tumours to HDAC-targeted treatment. Methods: A hybrid molecule, Roxyl-zhc-84 was designed and synthesized with novel architecture. The pharmacokinetics and toxicity of Roxyl-zhc-84 were analysed. The antitumour effects of Roxyl-zhc-84 on solid tumours were investigated by assessing cell growth, apoptosis and cell cycle in vitro and in three in vivo mouse models and compared to those of corresponding control inhibitors alone or in combination. Gene set enrichment analysis was performed, and relevant JAK1-STAT3-BCL2 signalling was identified in vitro and in vivo in mechanistic studies. Results: Roxyl-zhc-84 showed excellent pharmacokinetics and low toxicity. The novel hybrid inhibitor Roxyl-zhc-84 induced cell apoptosis and G1-phase arrest in breast cancer and ovarian cancer cell lines. In three mouse models, oral administration of Roxyl-zhc-84 led to significant tumour regression without obvious toxicity. Moreover, Roxyl-zhc-84 dramatically improved the limited response of traditional HDAC inhibitors in solid tumours via overcoming JAK1-STAT3-BCL2-mediated drug resistance. Roxyl-zhc-84 treatment exhibited vastly superior efficacy than the combination of HDAC and JAK1 inhibitors both in vitro and in vivo. Conclusion: Concurrent inhibition of HDAC and CDK using Roxyl-zhc-84 with additional JAK1 targeting resolved the limited response of traditional HDAC inhibitors in solid tumours via overcoming JAK1-STAT3-BCL2-mediated drug resistance, providing a rational multi-target treatment to sensitize solid tumours to HDACi therapy.