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

Abstract

UNLABELLED:

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.

• Authors: Terence Kin Wah Lee, Antonia Castilho, Vincent Chi Ho Cheung, Kwan Ho Tang, Stephanie Ma, Irene Oi Lin Ng
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 53 Issue 1 Pg. 160-70 (Jan 2011) ISSN: 1527-3350 [Electronic] United States
• PMID: 20979057 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 American Association for the Study of Liver Diseases.

Chemical References

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

Topics

• 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