Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor.
Ursolic acid (UA), a triterpenoid compound isolated previously from Oldenlandia diffusa, which is a Traditional Chinese Medicine used to treat cancer, was found to inhibit the proliferation of doxorubicin-resistant human hepatoma cell line (R-HepG2) through apoptosis as shown by externalization of phosphatidyl serine, morphological changes and loss of mitochondrial membrane potential. UA could activate Bak but not Bax, which implied that Bak may play an important role in UA-induced apoptosis. Furthermore, the death of R-HepG2 cells induced by UA was found to be mainly through the caspase-independent apoptosis-inducing factor (AIF) signaling pathway which was evidenced by: (a) the pan-caspase inhibitor and the specific caspase inhibitor had only modest protective effect against UA; (b) UA treatment caused the nuclear translocation of AIF, which is retained in the mitochondria in untreated R-HepG2 cells; (c) cells that had been treated with human AIF-specific siRNA could resist cell death induced by UA. In addition, a further animal study showed that UA was effective against R-HepG2 cells in vivo with negligible body weight loss and damage towards the liver, heart and spleen. Most importantly, immunohistochemical staining in animal tissues also suggested that UA also significantly inhibited the growth of R-HepG2 cells in nude mice through the AIF signaling pathway.
Yang
Lu
L
Research Center of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
Liu
Xiaozhuo
X
Lu
Zengbing
Z
Yuet-Wa Chan
Judy
J
Zhou
Linli
L
Fung
Kwok-Pui
KP
Wu
Ping
P
Wu
Shihua
S
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
D000972:Antineoplastic Agents, Phytogenic; D051033:Apoptosis Inducing Factor; D004317:Doxorubicin; D014315:Triterpenes; D000097245:Ursolic Acid