苯丁酸钠衍生的组蛋白去乙酰化酶抑制剂对肝癌的放射增敏作用。

Radiosensitizing effect of a phenylbutyrate-derived histone deacetylase inhibitor in hepatocellular carcinoma.

机构信息

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

出版信息

Int J Radiat Oncol Biol Phys. 2012 Jun 1;83(2):e181-9. doi: 10.1016/j.ijrobp.2011.12.022. Epub 2012 Feb 28.

DOI:10.1016/j.ijrobp.2011.12.022

PMID:22381897

Abstract

PURPOSE

Radiotherapy is integrated into the multimodal treatment of localized hepatocellular carcinoma (HCC) refractory to conventional treatment. Tumor control remains unsatisfactory and the sublethal effect associates with secondary spread. The use of an effective molecularly targeted agent in combination with radiotherapy is a potential therapeutic approach. Our aim was to assess the effect of combining a phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, AR-42, with radiotherapy in in vitro and in vivo models of human HCC.

METHODS AND MATERIALS

Human HCC cell lines (Huh-7 and PLC-5) were used to evaluate the in vitro synergism of combining AR-42 with irradiation. Flow cytometry analyzed the cell cycle changes, whereas Western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with AR-42 and/or radiotherapy for the in vivo response.

RESULTS

AR-42 significantly enhanced radiation-induced cell death by the inhibition of the DNA end-binding activity of Ku70, a highly versatile regulatory protein for DNA repair, telomere maintenance, and apoptosis. In ectopic xenografts of Huh-7 and PLC-5, pretreatment with AR-42 significantly enhanced the tumor-suppressive effect of radiotherapy by 48% and 66%, respectively. A similar combinatorial effect of AR-42 (10 and 25 mg/kg) and radiotherapy was observed in Huh-7 orthotopic model of tumor growth by 52% and 82%, respectively. This tumor suppression was associated with inhibition of intratumoral Ku70 activity as well as reductions in markers of HDAC activity and proliferation, and increased apoptosis.

CONCLUSION

AR-42 is a potent, orally bioavailable inhibitor of HDAC with therapeutic value as a radiosensitizer of HCC.

摘要

目的

放射疗法被整合到局部肝细胞癌（HCC）的多模式治疗中，这些 HCC 对常规治疗具有抗性。肿瘤控制仍然不尽如人意，亚致死效应与继发性扩散有关。使用有效的分子靶向药物与放射疗法联合使用是一种潜在的治疗方法。我们的目的是评估将苯丁酸钠衍生的组蛋白去乙酰化酶（HDAC）抑制剂 AR-42 与放射疗法联合用于体外和体内人 HCC 模型的效果。

方法和材料

人 HCC 细胞系（Huh-7 和 PLC-5）用于评估 AR-42 与照射联合使用的体外协同作用。流式细胞术分析细胞周期变化，而 Western blot 则研究联合处理后的蛋白质表达。携带异位和原位 HCC 异种移植的严重联合免疫缺陷（SCID）小鼠接受 AR-42 和/或放射治疗以评估体内反应。

结果

AR-42 通过抑制 Ku70 的 DNA 末端结合活性，显著增强了辐射诱导的细胞死亡，Ku70 是一种多功能的 DNA 修复、端粒维持和凋亡调节蛋白。在 Huh-7 和 PLC-5 的异位异种移植中，AR-42 的预处理分别显著增强了放疗的肿瘤抑制作用，分别增强了 48%和 66%。在 Huh-7 原位肿瘤生长模型中，AR-42（10 和 25 mg/kg）与放射疗法的类似组合效应分别增强了 52%和 82%。这种肿瘤抑制与抑制肿瘤内 Ku70 活性以及降低 HDAC 活性和增殖标志物以及增加凋亡有关。