Combined anti-tumor effects of IFN-α and sorafenib on hepatocellular carcinoma in vitro and in vivo

Hepatocellular carcinoma (HCC) is among the most common and aggressive cancers worldwide, and novel therapeutic strategies are urgently required to improve clinical outcome. Interferon-alpha (IFN-alpha) and sorafenib are widely used as anti-tumor agents against various malignancies. In this study, we investigated the combined effects of IFN-alpha and sorafenib against HCC. We demonstrated that the combination therapy synergistically suppressed HCC cellular viability; arrested cell cycle propagation and induced apoptosis in HCC cells. Further research revealed that IFN-alpha and sorafenib collaboratively regulated the expression levels of cell cycle-related proteins Cyclin A and Cyclin B as well as the pro-survival Bcl-2 family proteins Mcl-1, Bcl-2 and Bcl-X-L. Moreover, sorafenib inhibited IFN-alpha induced oncogenic signaling of STAT3, AKT and ERK but not the activation of the tumor suppressor STAT1. Xenograft experiments also confirmed the combined effects of IFN-alpha and sorafenib on tumor growth inhibition and apoptosis induction in vivo. In conclusion, these results provide rationale for the clinical application of IFN-alpha and sorafenib combination therapy in HCC treatment. (C) 2012 Elsevier Inc. All rights reserved.