RESUMEN
Liver cancer is a leading cause of cancerrelated 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 antihepatitis virus drugs, lamivudine and ribavirin, and one antiinfluenza 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 THLE3 cells in a dosedependent 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 Huh7 cells, as revealed by the significantly higher ratios of LC3II/LC3I, increased expression of Beclin1, and decreased expression of p62, whereas no significant increases in the expression of apoptosisrelated proteins, including Apaf1, cleaved caspase3, and cleaved PARP1, 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 Apaf1, cleaved caspase3, and cleaved PARP1, the higher ratios of LC3II/LC3I, the increased expression of Beclin1, and the decreased expression of p62. Additionally, significant inhibitory effects of oseltamivir on xenografted Huh7 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 in vitro and in vivo and may provide an alternative approach for treating liver cancer.