Background:
Sorafenib (Nexavar®) is an FDA-approved systemic
therapy for advanced
hepatocellular carcinoma (HCC). However, the low efficacy and adverse effects at high doses limit the clinical application of
sorafenib and strongly recommend its combination with other agents aiming at ameliorating its drawbacks.
OSU-2S, a PKCδ activator, was selected as a potential candidate
anticancer agent to be combined with
sorafenib to promote the anti-
cancer activity through synergistic interaction. Methods: The antitumor effects of
sorafenib,
OSU-2S and their combination were assessed by MTT assay,
caspase activation, Western blotting, migration/invasion assays in four different HCC cell lines. The synergistic interactions were determined by Calcusyn analysis. PKCδ knockdown was used to elucidate the role of PKCδ activation as a mechanism for the synergy. The knockdown/over-expression of p53 was used to explain the differential sensitivity of HCC cell lines to
sorafenib and/or
OSU-2S. Results:
OSU-2S synergistically enhanced the anti-proliferative effects of
sorafenib in the four used HCC cell lines with combination indices <1. This effect was accompanied by parallel increases in
caspase 3/7 activity, PARP cleavage, PKCδ activation and inhibition of HCC cell migration/invasion. In addition, PKCδ knockdown abolished the synergy between
sorafenib and
OSU-2S. Furthermore, p53 restoration in Hep3B cells through the over-expression rendered them more sensitive to both agents while p53 knockdown from HepG2 cells increased their resistance to both agents. Conclusion:
OSU-2S augments the anti-proliferative effect of
sorafenib in HCC cell lines, in part, through the activation of PKCδ. The p53 status in HCC cells predicts their sensitivity toward both
sorafenib and
OSU-2S. The proposed combination represents a therapeutically relevant approach that can lead to a new HCC therapeutic protocol.