Oleanolic acid and ursolic acid induce apoptosis in HuH7 human hepatocellular carcinoma cells through a mitochondrial-dependent pathway and downregulation of XIAP.
Oleanolic acid (OA) and ursolic acid (UA) are commonly found in plants and herbs and have been reported to possess hepatoprotective, anti-inflammatory and anticancer activities. In the present study, the effects of OA and UA on induction of apoptosis in human hepatocellular carcinoma HuH7 cells and the related mechanisms were investigated. The results demonstrate that OA and UA could inhibit the growth of HuH7 cells with IC(50) values of 100 and 75 microM, respectively. Cell cycle analysis using flow cytometry indicated that the fraction of HuH7 cells in sub-G1 phase progressively increased with increasing concentrations of OA or UA from 20 to 80 microM. Treatment with OA and UA for 8 h induced a dramatic loss of the mitochondria membrane potential and interfered with the ratio of expression levels of pro- and antiapoptotic Bcl-2 family members in HuH7 cells. OA and UA-induced apoptosis involving the release of mitochondria cytochrome c into the cytosol and subsequently induced the activation of caspase-9 and caspase-3, followed by cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, HuH7 cells treated with OA and UA suppressed the activity of NF-kappaB and modulated the mRNA expression of X-linked inhibitor of apoptotic protein (XIAP) as compared with untreated cells. These results demonstrate that OA and UA induce apoptosis in HuH7 cells through a mitochondria-mediated pathway and downregulation of XIAP.
Shyu
Ming-Huan
MH
Department of Food Science and Biotechnology, National Chung Hsing University, 250 Kuokuang Road, Taiching 402, Taiwan.
Kao
Tzu-Chien
TC
Yen
Gow-Chin
GC
D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009828:Oleanolic Acid / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics*; D000097245:Ursolic Acid
D020169:Caspases; D016328:NF-kappa B; D009828:Oleanolic Acid; D014315:Triterpenes; D051636:X-Linked Inhibitor of Apoptosis Protein; D000097245:Ursolic Acid; C496866:XIAP protein, human