Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
Int J Cancer. 2014 Jul 15;135(2):492-501. doi: 10.1002/ijc.28682. Epub 2014 Jan 10.
Radiotherapy has been integrated into the multimodal treatment of hepatocellular carcinoma (HCC), especially of localized hepatic tumor(s) refractory to conventional treatment. However, tumor control remains unsatisfactory mainly because of insufficient dose, and sublethally irradiated tumor may associate with metastasis. Our aim was to assess the effect of combining a molecularly targeted Aurora kinase inhibitor, VE-465, with radiotherapy in in vitro and in vivo models of human HCC. Human HCC cell lines (Huh7 and PLC-5) were used to evaluate the in vitro synergism of combining VE-465 with irradiation. Flow cytometry analyzed the cell cycle changes, while western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with VE-465 and/or radiotherapy for the in vivo response. VE-465 significantly enhanced radiation-induced death in HCC cells by a mechanism involving the enhanced inhibition of histone H3 phosphorylation and interruption of cell cycle change. In SCID, mice bearing ectopic HCC xenografts, pretreatment with VE-465 (20 mg/kg/day × 9 days) significantly enhanced the tumor-suppressive effect of radiotherapy (5 Gy/day × 5 days) by 54.0%. A similar combinatorial effect of VE-465 and radiotherapy was observed in an orthotopic model of Huh7 tumor growth by 17.2%. In the orthotopic Huh7 xenografts, VE-465 significantly enhanced radiation-induced tumor growth suppression by a mechanism involving the increased apoptosis. VE-465 is a potent inhibitor of Aurora kinase with therapeutic value as a radiosensitizer of HCC.
放射治疗已被整合到肝细胞癌（HCC）的多模态治疗中，尤其是对于常规治疗难治的局部肝肿瘤。然而，肿瘤控制仍然不尽如人意，主要是由于剂量不足，并且亚致死性照射的肿瘤可能与转移有关。我们的目的是评估在体外和体内 HCC 模型中联合使用一种分子靶向 Aurora 激酶抑制剂 VE-465 与放射治疗的效果。我们使用人 HCC 细胞系（Huh7 和 PLC-5）来评估 VE-465 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 则在联合治疗后检测蛋白质表达。严重联合免疫缺陷（SCID）小鼠带有异位和原位 HCC 异种移植瘤，并用 VE-465 和/或放射治疗进行体内反应。VE-465 通过增强抑制组蛋白 H3 磷酸化和中断细胞周期变化的机制，显著增强 HCC 细胞对辐射诱导的死亡。在 SCID 小鼠中，在异位 HCC 异种移植瘤中，VE-465 预处理（20 mg/kg/天×9 天）显著增强了放疗（5 Gy/天×5 天）的肿瘤抑制作用，增强了 54.0%。在 Huh7 肿瘤生长的原位模型中观察到类似的 VE-465 和放疗联合作用，增强了 17.2%。在原位 Huh7 异种移植瘤中，VE-465 通过增加细胞凋亡的机制，显著增强了辐射诱导的肿瘤生长抑制作用。VE-465 是一种有效的 Aurora 激酶抑制剂，具有作为 HCC 放射增敏剂的治疗价值。
