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.


CONCLUSIONS
Our results suggest that lupeol may be an effective dietary phytochemical that targets liver T-ICs.
State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
Terence Kin Wah
TK
Lee
Antonia
A
Castilho
Vincent Chi Ho
VC
Cheung
Kwan Ho
KH
Tang
Stephanie
S
Ma
Irene Oi Lin
IO
Ng
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006023:Glycoproteins; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000502:physiology; D053978:Pentacyclic Triterpenes / Q000627:therapeutic use*; D010455:Peptides; D000094042:Lupanes
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D051059:PTEN Phosphohydrolase; D053978:Pentacyclic Triterpenes; D010455:Peptides; C000606023:PROM1 protein, human; C000606024:Prom1 protein, mouse; C487757:Pten protein, mouse; C010480:lupeol; D000094042:Lupanes