NSC 74859-mediated inhibition of STAT3 enhances the anti-proliferative activity of cetuximab in hepatocellular carcinoma.

Abstract

BACKGROUND:

Cetuximab [an epidermal growth factor receptor (EGFR) inhibitor], which was shown to be effective in rectal and non-small cell lung cancers (NSCLCs), was only modestly effective in clinical trials of hepatocellular carcinoma (HCC). STAT3, which is thought to be a determinant of HCC sensitivity to antitumour drugs, may be involved.

AIMS:

To evaluate the efficacy of combination therapy using cetuximab and NSC 74859 (a novel STAT3 inhibitor) in EGFR and STAT3 overexpressing hepatoma cells.

METHODS:

Hepatoma cell lines were treated with cetuximab, NSC 74859 or a combination of both drugs. Efficacy of treatment was evaluated by determining cell viability using MTT assays and proliferation by cell counting. Expression and activation of STAT3 were determined using Western blot analysis. We evaluated the role of STAT3 in single and combination therapy using siRNA-mediated knock-down of STAT3 or STAT3 overexpression strategies.

RESULTS:

HepG2 and Huh-7 cells, which had lower levels of pSTAT3 than SK-HEP1 cells, were more sensitive to cetuximab treatment when compared with SK-HEP1 cells. Although none of these cell lines was sensitive to NSC 74859 alone, NSC 74859 potentiated the antiproliferative effect of cetuximab in all three cell lines. siRNA knock-down of STAT3 increased the sensitivity of these cell lines to cetuximab, whereas STAT3 overexpression antagonized these effects.

CONCLUSIONS:

Enhanced growth inhibition in hepatoma cells treated with both NSC 74859 and cetuximab suggests that cetuximab resistance is probably mediated via STAT3. Combination therapy using both inhibitors of EGFR and STAT3 signalling warrants further investigation under in vivo condition.

• Authors: Wei Chen, Xuning Shen, Xuefeng Xia, Guodong Xu, Tao Ma, Xueli Bai, Tingbo Liang
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 32 Issue 1 Pg. 70-7 (Jan 2012) ISSN: 1478-3231 [Electronic] United States
• PMID: 22098470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 John Wiley & Sons A/S.

Chemical References

• Aminosalicylic Acids
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Benzenesulfonates
• NSC 74859
• STAT3 Transcription Factor
• STAT3 protein, human
• Tetrazolium Salts
• Thiazoles
• thiazolyl blue
• Cetuximab

Topics

• Aminosalicylic Acids (pharmacology)
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacology)
• Benzenesulfonates (pharmacology)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cetuximab
• Drug Screening Assays, Antitumor
• Drug Synergism
• Hepatocytes (drug effects, metabolism, pathology)
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Tetrazolium Salts (metabolism)
• Thiazoles (metabolism)
• Transfection