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

Background: Interferon-gamma (IFN-gamma) 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-gamma, due mainly to down-regulation of IFN-gamma receptor chain 2 (IFN-gamma R2), even though IFN-gamma receptor chain 1 (IFN-,yRl), the domain that includes the binding site of IFN-7, 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-gamma R2 and enhance the anti-proliferative effect of IFN-gamma. Methods: Two HCC cell lines, HuH7 and SNU449, were treated with the iron-chelating agent deferoxamine (DFO), IFN-gamma, and/or anti-hIGF1R blocking antibody. The expression of IFN-gamma R1 and IFN-gamma R2 was then evaluated by flow cytometry and Western blotting. The anti-proliferative effect of IFN-gamma was investigated by MTT assay, and the pro-apoptotic effect was investigated by annexin-V flow cytometry. Results: DFO and blocking with anti-hIGF1R antibody increased the expression of IFN-gamma R2, but the effect on IFN-gamma R1 expression was less marked. DFO, anti-hIGF1R blocking antibody, or both directly enhanced the anti-proliferative effect of IFN-gamma through increased pro-apoptotic activity. Conclusion: The present results indicate that IFN-gamma reinforced by iron modulation could be a promising new therapeutic approach for HCC. (c) 2006 Elsevier Ireland Ltd. All rights reserved.