Deferoxamine enhances anti-proliferative effect of interferon-gamma 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-gammaR2), even though IFN-gamma receptor chain 1 (IFN-gammaR1), the domain that includes the binding site of IFN-gamma, 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-gammaR2 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-gammaR1 and IFN-gammaR2 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-gammaR2, but the effect on IFN-gammaR1 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.


CONCLUSIONS
The present results indicate that IFN-gamma reinforced by iron modulation could be a promising new therapeutic approach for HCC.
Okada
Toshie
T
Second Department of Surgery, Dokkyo University School of Medicine, Kitakobayashi 880, Mibu, Shimotsuga, Tochigi 321-0293, Japan.
Sawada
Tokihiko
T
Kubota
Keiichi
K
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology*; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D000096743:Interferon gamma Receptor
D003676:Deferoxamine; D007371:Interferon-gamma; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C086185:IFNGR2 protein, human; C494079:STAT1 protein, human