Department of Family Medicine, Changhua Christian Hospital, Changhua 500, Taiwan, R.O.C.
Department of Neurology and Department of Medical Intensive Care Unit, Changhua Christian Hospital, Changhua 500, Taiwan, R.O.C.
Int J Oncol. 2021 Dec;59(6). doi: 10.3892/ijo.2021.5289. Epub 2021 Dec 3.
Liver cancer is a leading cause of cancer‑related mortality globally. Since hepatitis virus infections have been strongly associated with the incidence of liver cancer, studies concerning the effects of antiviral drugs on liver cancer have attracted great attention in recent years. The present study investigated the effects of two anti‑hepatitis virus drugs, lamivudine and ribavirin, and one anti‑influenza virus drug, oseltamivir, on liver cancer cells to assess alternative methods for treating liver cancer. MTT assays, wound healing assays, Τranswell assays, flow cytometry, immunoblotting, ELISA, immunofluorescence staining and a xenograft animal model were adopted to verify the effects of lamivudine, ribavirin and oseltamivir on liver cancer cells. Treatment with ribavirin and oseltamivir for 24 and 48 h significantly decreased the viability of both Huh-7 and HepG2 cells compared with that of THLE‑3 cells in a dose‑dependent manner. The subsequent investigations focused on oseltamivir, considering the more serious clinical adverse effects of ribavirin than those of oseltamivir. Significantly decreased migration and invasion were observed in both Huh-7 and HepG2 cells that were treated with oseltamivir for 24 and 48 h. In addition, oseltamivir significantly increased autophagy in Huh‑7 cells, as revealed by the significantly higher ratios of LC3‑II/LC3‑I, increased expression of Beclin‑1, and decreased expression of p62, whereas no significant increases in the expression of apoptosis‑related proteins, including Apaf‑1, cleaved caspase‑3, and cleaved PARP‑1, were detected. Notably, apoptosis and autophagy were significantly increased in HepG2 cells in the presence of oseltamivir, as revealed by the significant increases in the expression of Apaf‑1, cleaved caspase‑3, and cleaved PARP‑1, the higher ratios of LC3‑II/LC3‑I, the increased expression of Beclin‑1, and the decreased expression of p62. Additionally, significant inhibitory effects of oseltamivir on xenografted Huh‑7 cells in athymic nude mice were observed. The present study, for the first time to the best of our knowledge, reported the differential effects of oseltamivir on inducing liver cancer cell death both and and may provide an alternative approach for treating liver cancer.
肝癌是全球癌症相关死亡的主要原因。由于肝炎病毒感染与肝癌的发生有很强的相关性，近年来，关于抗病毒药物对肝癌影响的研究引起了极大关注。本研究探讨了两种抗肝炎病毒药物拉米夫定和利巴韦林以及一种抗流感病毒药物奥司他韦对肝癌细胞的影响，以评估治疗肝癌的替代方法。采用 MTT 检测、划痕愈合检测、Transwell 检测、流式细胞术、免疫印迹、ELISA、免疫荧光染色和异种移植动物模型来验证拉米夫定、利巴韦林和奥司他韦对肝癌细胞的作用。结果发现，利巴韦林和奥司他韦处理 24 和 48 h 后，与 THLE-3 细胞相比，两种 Huh-7 和 HepG2 细胞的活力均呈剂量依赖性显著降低。由于利巴韦林的临床不良反应比奥司他韦更严重，因此后续研究集中在奥司他韦上。结果发现，奥司他韦处理 Huh-7 和 HepG2 细胞 24 和 48 h 后，迁移和侵袭均显著减少。此外，奥司他韦显著增加了 Huh-7 细胞中的自噬，LC3-II/LC3-I 比值显著升高，Beclin-1 表达增加，p62 表达减少，而凋亡相关蛋白，包括 Apaf-1、cleaved caspase-3 和 cleaved PARP-1 的表达没有显著增加。值得注意的是，奥司他韦处理 HepG2 细胞后，凋亡和自噬均显著增加，Apaf-1、cleaved caspase-3 和 cleaved PARP-1 的表达显著增加，LC3-II/LC3-I 比值升高，Beclin-1 表达增加，p62 表达减少。此外，奥司他韦对裸鼠皮下移植 Huh-7 细胞也有显著的抑制作用。本研究首次报道了奥司他韦对肝癌细胞死亡的不同作用，为治疗肝癌提供了一种新的方法。
