Sodium butyrate enhances STAT 1 expression in PLC/PRF/5 hepatoma cells and augments their responsiveness to interferon-alpha.
Although interferon-alpha (IFN-alpha) has shown great promise in the treatment of chronic viral hepatitis, the anti-tumour effect of this agent in the therapy of liver cancer is unclear. Recent studies have demonstrated that differentiation-inducing agents could modulate the responsiveness of cancer cells to IFN-alpha by regulating the expression of signal transducers and activators of transcription (STAT) proteins, a group of transcription factors which play important roles in the IFN signalling pathway. We have reported that sodium butyrate is a potent differentiation inducer for human hepatoma cells. In this study, we investigated whether this drug could regulate the expression of STAT proteins and enhance the anti-tumour effect of IFN-alpha in hepatoma cells. We found that sodium butyrate specifically activated STAT1 gene expression and enhanced IFN-alpha-induced phosphorylation and activation of STAT1 proteins. Co-treatment with these two drugs led to G1 growth arrest, accompanied by down-regulation of cyclin D1 and up-regulation of p21WAF-1, and accumulation of hypophosphorylated retinoblastoma protein in hepatoma cells. Additionally, internucleosomal DNA fragmentation, a biological hallmark of apoptosis, was detected in hepatoma cells after continuous incubation with a combination of these two drugs for 72 h. Our results show that sodium butyrate potently enhances the anti-tumour effect of IFN-alpha in vitro and suggest that a rational combination of these two drugs may be useful for the treatment of liver cancer.
Hung
W C
WC
School of Technology for Medical Sciences, Kaohsiung Medical College, Taiwan, Republic of China.
Chuang
L Y
LY
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020148:Butyric Acid / Q000008:administration & dosage / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000378:metabolism; D010766:Phosphorylation; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000096:biosynthesis* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007370:Interferon Type I; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D020148:Butyric Acid