Deferoxamine enhances anti-proliferative effect of interferon-γ against hepatocellular carcinoma cells

BackgroundInterferon-γ (IFN-γ) is a multifunctional cytokine, whose anti-proliferative effect is expected to be of therapeutic value against human cancer. However, hepatocellular carcinoma (HCC) shows resistance to the anti-proliferative effect of IFN-γ, due mainly to down-regulation of IFN-γ receptor chain 2 (IFN-γR2), even though IFN-γ receptor chain 1 (IFN-γR1), the domain that includes the binding site of IFN-γ, is stably expressed. The aims of this study were to investigate whether iron chelation, blocking of the human insulin-like growth factor-1 receptor (hIGF1R), or both could upregulate IFN-γR2 and enhance the anti-proliferative effect of IFN-γ.MethodsTwo HCC cell lines, HuH7 and SNU449, were treated with the iron-chelating agent deferoxamine (DFO), IFN-γ, and/or anti-hIGF1R blocking antibody. The expression of IFN-γR1 and IFN-γR2 was then evaluated by flow cytometry and Western blotting. The anti-proliferative effect of IFN-γ was investigated by MTT assay, and the pro-apoptotic effect was investigated by annexin-V flow cytometry.ResultsDFO and blocking with anti-hIGF1R antibody increased the expression of IFN-γR2, but the effect on IFN-γR1 expression was less marked. DFO, anti-hIGF1R blocking antibody, or both directly enhanced the anti-proliferative effect of IFN-γ through increased pro-apoptotic activity.ConclusionThe present results indicate that IFN-γ reinforced by iron modulation could be a promising new therapeutic approach for HCC.