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

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. Our results suggest that lupeol may be an effective dietary phytochemical that targets liver T-ICs. Copyright © 2010 American Association for the Study of Liver Diseases.

Citation

Terence Kin Wah Lee, Antonia Castilho, Vincent Chi Ho Cheung, Kwan Ho Tang, Stephanie Ma, Irene Oi Lin Ng. Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation. Hepatology (Baltimore, Md.). 2011 Jan;53(1):160-70

Mesh Tags

Substances

PMID: 20979057

search → result