Inhibitory effects of Silibinin combined with doxorubicin in hepatocellular carcinoma; an in vivo study

J BUON. 2016 Jul-Aug;21(4):917-924.


Purpose: Hepatocellular carcinoma (HCC) is the one of the most common cancers and the third leading cause of cancer related mortality in the world. Unacceptable side effect and development of treatment resistance are the major concerns with the conventional chemotherapeutic agents. Combination therapy using phytotherapeutic agents is attracting the attention of investigators in view of the current needs.

Methods: In the present study we have evaluated the synergistic effect of silibinin, a nontoxic phytotherapeutic agent in combination with doxorubicin, in advanced HCC using HEPG2 cells and an orthotopic rat model of HCC.

Results: The results showed that silibinin strongly synergized with doxorubicin-induced growth inhibition, G2-M arrest, and apoptosis of HEPG2 cells. Silibinin-doxorubicin combination also inhibited cdc2/p34 kinase activity when histone H1 was used as substrate. The combination regimen also moderately increased the expression of cdc25C-cyclin B1-cdc2/p34 associated upstream kinases (Chk1). Simultaneous treatment with silibinin-doxorubicin combination showed a 41% increase in the apoptotic cell death (p=0.01), which was 3-fold higher than what was observed with silibinin or doxorubicin individually. In the orthotopic rat model treatment with silibinin-doxorubicin reduced tumor growth by close to 30% at nearly twice lower dose of individual drugs in the combination group.

Conclusions: Our study suggests that combination therapy using silibinin-doxorubicin may show a better therapeutic efficacy in patients with HCC. These findings need to be further validated in human clinical trials.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation / drug effects
  • Doxorubicin / administration & dosage
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Male
  • Rats
  • Silybin
  • Silymarin / administration & dosage
  • Tumor Cells, Cultured


  • Cell Cycle Proteins
  • Silymarin
  • Silybin
  • Doxorubicin