Cytotoxicity of berberine on human cervical carcinoma HeLa cells through mitochondria, death receptor and MAPK pathways, and in-silico drug-target prediction

Toxicol In Vitro. 2010 Sep;24(6):1482-90. doi: 10.1016/j.tiv.2010.07.017. Epub 2010 Jul 23.


Berberine, a natural product, has been widely used to treat hyperlipoidemia and intestinal diseases. In the present paper, berberine showed a significant anti-proliferative effect to human cervical carcinoma HeLa cells confirmed by 3-(4,5)-dimethyl-thiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT), flow cytometry analysis (FCM) and so on. The methods including western blotting, radioimmunity assay (RIA), reverse transcription-polymerase chain reaction (RT-PCR) were used to investigate protein and mRNA expressions. We found that Bcl-2/Bax ratio was significantly decreased and cytochrome c was released from mitochondrion to cytosol, which indicated that the mitochondrial pathway was activated by berberine. The up-regulation of Fas, FasL, TNF-alpha and TRAF-1 indicated the involvement of the death receptor pathway in the process of berberine-induced apoptosis. Furthermore caspase-3 and caspase-8 were activated as a central event of apoptosis, and the levels of phosphorylation of mitogen-activated protein kinases (MAPKs) were also investigated. In addition, the increased expression of p53 was also observed in berberine-treated HeLa cells, and as a node point of these different pathways in a protein-protein interaction network constructed by GeneGo software, p53 might be the possible drug-target of berberine's anti-cancer on HeLa cells, which was predicted by a flexible ligand-protein inverse docking program, INVDOCK. This study is benefit for clarifying the mechanism of berberine's anti-tumor effect and might be helpful to find therapy-target for treatment of human cervical carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Berberine / pharmacology*
  • Cell Survival / drug effects
  • Computational Biology
  • Drug Discovery
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism
  • Female
  • Gene Expression
  • HeLa Cells
  • Humans
  • Mitochondria / drug effects*
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • RNA, Messenger / metabolism
  • Receptors, Death Domain / metabolism*
  • TNF Receptor-Associated Factor 1 / genetics
  • TNF Receptor-Associated Factor 1 / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Stem Cell Assay
  • Uterine Cervical Neoplasms / drug therapy*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology
  • fas Receptor / genetics
  • fas Receptor / metabolism


  • Antineoplastic Agents
  • FASLG protein, human
  • Fas Ligand Protein
  • RNA, Messenger
  • Receptors, Death Domain
  • TNF Receptor-Associated Factor 1
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Berberine
  • Mitogen-Activated Protein Kinase Kinases