1. Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun 130021, China;
2. The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
Background: Currently, sorafenib is the only systemic chemotherapy drug for advanced stage Hepatocellular carcinoma (HCC). However, emerging data from some clinical HCC patients indicate that sorafenib alone has only moderate antitumor efficacy, and could not inhibit disease metastasis and progression. KU-55933 is a specific ATM inhibitor, which has pro-apoptotic effect on tumor cells. In this study, we analyzed the synergistic effect of sorafenib and KU-55933 on the proliferation of HCC cell lines.
Methods: Three HCC cell lines were treated with sorafenib and KU-55933 alone or combination in vitro to investigate inhibitory effect by MTT and wound healing assay. Epithelial to mesenchymal transition (EMT) phenotype change was investigated after sorafenib and KU-55933 treatment by microscopy. Akt signaling pathway proteins including p-Akt, p-mTOR and p-p70S6K were examined by western blot. In addition, cleaved PARP and autophage-related proteins LC3A/B were detected by western blot.
Results: KU-55933 can enhance the effect of sorafenib in inhibiting cell proliferation and migration, overcoming EMT, inducing cell apoptosis via inactivating Akt signaling pathway and inducing autophage. The combination treatment with sorafenib and KU-55933 resulted in a strong synergistic effect in vitro.
Conclusion: Our results demonstrate that sorafenib combined with KU-55933 treatment does effectively inhibit proliferation of HCC cell lines synergistically. These data suggests that KU-55933 may be a promising chemosensitizer to sorafenib in the treatment of HCC.
Keywords: Hepatocellular carcinoma, sorafenib, KU-55933, EMT, migration, autophage.