Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Department of Biomedical Science and Technology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
J Gastroenterol. 2020 Nov;55(11):1072-1086. doi: 10.1007/s00535-020-01705-8. Epub 2020 Jul 14.
The prognosis for patients with unresectable advanced hepatocellular carcinoma (HCC) is poor. Miriplatin is a hydrophobic platinum compound that has a long retention time in lesions after transarterial chemoembolization (TACE). We investigated anti-tumor activity of miriplatin combined with irradiation on HCC cells, and its underlying mechanism of apoptosis. We also analyzed the effectiveness of miriplatin-TACE and radiotherapy for locally advanced HCC.
Human HCC cell lines HepG2 and HuH-7 were treated with DPC (active form of miriplatin) and radiation, and synergy was evaluated using a combination index (CI). Apoptosis-related proteins and cell cycles were analyzed by western blotting and flowcytometry. We retrospectively analyzed treatment outcomes in 10 unresectable HCC patients with vascular/bile duct invasion treated with miriplatin-TACE and radiotherapy.
DPC or X-ray irradiation decreased cell viability dose-dependently. DPC plus irradiation decreased cell viability synergistically in both cell lines (CI < 1, respectively). Cleaved PARP expression was induced much more strongly by DPC plus irradiation than by each treatment alone. Expression of p53 up-regulated modulator of apoptosis (PUMA) was significantly induced by the combination, and knockdown of PUMA with siRNA significantly decreased apoptosis in both cell lines. DPC plus irradiation caused sub-G1, G2/M, and S phase cell arrest in those cells. The combination of miriplatin-TACE and radiotherapy showed a high response rate for patients with locally advanced HCC despite small number of patients.
Miriplatin plus irradiation had synergistic anti-tumor activity on HCC cells through PUMA-mediated apoptosis and cell cycle arrest. This combination may possibly be effective in treating locally advanced HCC.
不可切除的晚期肝细胞癌（HCC）患者的预后较差。米立铂是一种疏水性铂化合物，在经动脉化疗栓塞（TACE）后在病变部位的保留时间较长。我们研究了米立铂联合放疗对 HCC 细胞的抗肿瘤活性及其凋亡的潜在机制。我们还分析了米立铂-TACE 和放疗治疗局部晚期 HCC 的疗效。
用 DPC（米立铂的活性形式）和辐射处理人 HCC 细胞系 HepG2 和 HuH-7，并使用组合指数（CI）评估协同作用。通过 Western blot 和流式细胞术分析凋亡相关蛋白和细胞周期。我们回顾性分析了 10 例不可切除的 HCC 患者（伴血管/胆管侵犯）接受米立铂-TACE 和放疗的治疗结果。
DPC 或 X 射线照射剂量依赖性地降低细胞活力。DPC 加照射在两种细胞系中协同降低细胞活力（CI<1）。与单独治疗相比，DPC 加照射诱导的 PARP 裂解表达要强得多。PUMA（凋亡上调调节剂）的表达在联合治疗中明显增加，并且用 siRNA 敲低 PUMA 会显著减少两种细胞系中的凋亡。DPC 加照射导致这些细胞的亚 G1、G2/M 和 S 期细胞停滞。尽管患者数量较少，但米立铂-TACE 和放疗的联合治疗对局部晚期 HCC 患者显示出较高的反应率。
米立铂联合放疗通过 PUMA 介导的凋亡和细胞周期阻滞对 HCC 细胞具有协同抗肿瘤活性。这种联合治疗可能对治疗局部晚期 HCC 有效。
