Ursolic Acid from Oldenlandia diffusa Induces Apoptosis via Activation of Caspases and Phosphorylation of Glycogen Synthase Kinase 3 Beta in SK-OV-3 Ovarian Cancer Cells
Open Access
- 1 January 2012
- journal article
- Published by Pharmaceutical Society of Japan in Biological & Pharmaceutical Bulletin
- Vol. 35 (7), 1022-1028
- https://doi.org/10.1248/bpb.b110660
Abstract
Although ursolic acid isolated from Oldenlandia diffusa (Rubiaceae) was known to have anticancer activities in prostate, breast and liver cancers, the underlying mechanism of ursolic acid in ovarian cancer cells was not investigated so far. In the present study, the apoptotic mechanism of ursolic acid was elucidated in SK-OV-3 ovarian cancer cells by 2,3-bis(2-methoxy-4-nitro-5-sulphophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay, cell cycle analysis and Western blotting. Ursolic acid exerted cytotoxicity against SK-OV-3 and A2780 ovarian cancer cells with IC50 of ca. 50 and 65 µM, respectively. Apoptotic bodies were observed in ursolic acid treated SK-OV-3 cells. Also, ursolic acid significantly increased ethidium homodimer stained cells and sub-G1 apoptotic portion in SK-OV-3 cells. Consistently, Western blotting revealed that ursolic acid effectively cleaved poly(ADP-ribose) polymerase (PARP), caspase-9 and -3, suppressed the expression of survival genes such as c-Myc, Bcl-xL and astrocyte elevated gene (AEG)-1, and upregulated phosphorylation of extracellular signal-regulated kinase (ERK) in SK-OV-3 cells. Interestingly, ursolic acid suppressed β-catenin degradation as well as enhanced phosphorylation of glycogen synthase kinase 3 beta (GSK 3β). Furthermore, GSK 3β inhibitor SB216763 blocked the cleavages of caspase-3 and PARP induced by ursolic acid and proteosomal inhibitor MG132 disturbed down-regulation of β-catenin, activation of caspase-3 and decreased mitochondrial membrane potential (MMP) induced by ursolic acid in SK-OV-3 cells. Overall, our findings suggest that ursolic acid induces apoptosis via activation of caspase and phosphorylation of GSK 3β in SK-OV-3 cancer cells as a potent anti-cancer agent for ovarian cancer therapy.Keywords
This publication has 22 references indexed in Scilit:
- Epidermal growth factor receptor blockers for the treatment of ovarian cancerEmergencias, 2011
- Inhibition of CXCR4/CXCL12 signaling axis by ursolic acid leads to suppression of metastasis in transgenic adenocarcinoma of mouse prostate modelInternational Journal of Cancer, 2011
- Targeting c-Myc as a novel approach for hepatocellular carcinomaWorld Journal of Hepatology, 2010
- Effects of ursolic acid on the proliferation and apoptosis of human ovarian cancer cellsJournal of Huazhong University of Science and Technology [Medical Sciences], 2009
- Ursolic Acid Triggers Apoptosis and Bcl-2 Downregulation in MCF-7 Breast Cancer CellsCancer Investigation, 2009
- Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-κB mediated activation of bcl-2 in B16F-10 melanoma cellsInternational Immunopharmacology, 2008
- Pharmacogenomic and Pharmacokinetic Determinants of Erlotinib ToxicityJournal of Clinical Oncology, 2008
- The c-Myc target gene networkSeminars in Cancer Biology, 2006
- Production of bioactive triterpenes by Eriobotrya japonica calliPhytochemistry, 2002
- Antitumour effects of ursolic acid isolated fromOldenlandia diffusaPhytotherapy Research, 1998