Clin Mol Hepatol.  2015 Mar;21(1):49-59. 10.3350/cmh.2015.21.1.49.

Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells

• Gu HR
• Park SC
• Choi SJ
• Lee JC
• Kim YC
• Han CJ
• Kim J
• Yang KY
• Kim YJ
• Noh GY
• No SH
• Jeong JH

• KMID: 2155291
• DOI: http://doi.org/10.3350/cmh.2015.21.1.49

Abstract

BACKGROUND/AIMS
Silibinin, the main component of silymarin, is used as a hepatoprotectant and exhibits anticancer effects against various cancer cells. This study evaluated the effects of a combination of silibinin with either gefitinib or sorafenib on hepatocellular carcinoma (HCC) cells.
METHODS
Several different human HCC cell lines were used to test the growth-inhibiting effects and cell toxicity of silibinin both alone and in combination with either gefitinib or sorafenib. The cell viability and growth inhibition were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and a colony-forming assay. Furthermore, changes in epidermal growth factor receptor (EGFR)-related signals were evaluated by Western blot analysis.
RESULTS
Gefitinib, sorafenib, and silibinin individually exhibited dose-dependent antiproliferative effects on HCC cells. Combined treatment with silibinin enhanced the gefitinib-induced growth-inhibiting effects in some HCC cell lines. The combination effect of gefitinib and silibinin was synergistic in the SNU761 cell line, but was only additive in the Huh-BAT cell line. The combination effect may be attributable to inhibition of EGFR-dependent Akt signaling. Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin.
CONCLUSIONS
Combined treatment with silibinin enhanced the growth-inhibiting effects of both gefitinib and sorafenib. Therefore, the combination of silibinin with either sorafenib or gefitinib could be a useful treatment approach for HCC in the future.

Keyword

Silibinin; Gefitinib; Sorafenib; Hepatocellular carcinoma

MeSH Terms

Antineoplastic Agents/*pharmacology
Carcinoma, Hepatocellular/metabolism/pathology
Cell Line, Tumor
Cell Proliferation/*drug effects
Cell Survival/drug effects
Down-Regulation/drug effects
Drug Screening Assays, Antitumor
Drug Synergism
Humans
Liver Neoplasms/metabolism/pathology
Niacinamide/*analogs & derivatives/pharmacology
Phenylurea Compounds/*pharmacology
Proto-Oncogene Proteins c-akt/metabolism
Quinazolines/*pharmacology
Receptor, Epidermal Growth Factor/metabolism
Signal Transduction/drug effects
Silymarin/*pharmacology
Antineoplastic Agents
Phenylurea Compounds
Quinazolines
Silymarin
Niacinamide
Proto-Oncogene Proteins c-akt
Receptor, Epidermal Growth Factor