Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation

Hepatology. 2011 Jan;53(1):160-70. doi: 10.1002/hep.24000. Epub 2010 Oct 26.


Liver tumor-initiating cells (T-ICs) are capable of self-renewal and tumor initiation and are more chemoresistant to chemotherapeutic drugs. The current therapeutic strategies for targeting stem cell self-renewal pathways therefore represent rational approaches for cancer prevention and treatment. In the present study, we found that Lup-20(29)-en-3β-ol (lupeol), a triterpene found in fruits and vegetables, inhibited the self-renewal ability of liver T-ICs present in both hepatocellular carcinoma (HCC) cell lines and clinical HCC samples, as reflected by hepatosphere formation. Furthermore, lupeol inhibited in vivo tumorigenicity in nude mice and down-regulated CD133 expression, which was previously shown to be a T-IC marker for HCC. In addition, lupeol sensitized HCC cells to chemotherapeutic agents through the phosphatase and tensin homolog (PTEN)-Akt-ABCG2 pathway. PTEN plays a crucial role in the self-renewal and chemoresistance of liver T-ICs; down-regulation of PTEN by a lentiviral-based approach reversed the effect of lupeol on liver T-ICs. Using an in vivo chemoresistant HCC tumor model, lupeol dramatically decreased the tumor volumes of MHCC-LM3 HCC cell line-derived xenografts, and the effect was equivalent to that of combined cisplatin and doxorubicin treatment. Lupeol exerted a synergistic effect without any adverse effects on body weight when combined with chemotherapeutic drugs.

Conclusion: Our results suggest that lupeol may be an effective dietary phytochemical that targets liver T-ICs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Animals
  • Antigens, CD
  • Carcinoma, Hepatocellular / drug therapy*
  • Cell Division / drug effects
  • Drug Resistance, Neoplasm
  • Glycoproteins
  • Humans
  • Liver Neoplasms / drug therapy*
  • Mice
  • Neoplasm Transplantation
  • PTEN Phosphohydrolase / physiology
  • Pentacyclic Triterpenes / therapeutic use*
  • Peptides


  • AC133 Antigen
  • Antigens, CD
  • Glycoproteins
  • PROM1 protein, human
  • Pentacyclic Triterpenes
  • Peptides
  • Prom1 protein, mouse
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • lupeol