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The Induction of Orphan Nuclear Receptor Nur77 Expression by n-Butylenephthalide as Pharmaceuticals on Hepatocellular Carcinoma Cell Therapy

Graduate Institute of Biotechnology (Y.-L.C., M.-H.J.) and Department of Applied Animal Science (C.-C.L.), National Ilan University, Ilan, Taiwan, Republic of China; Division of Colon and Rectum Surgery, Department of Surgery, Buddhist Tzu-Chi General Hospital (J.-C.K.) and Institute of Medical Sciences (S.-P.C.), Buddhist Tzu-Chi University, Hualien, Taiwan, Republic of China; Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China (P.-C.L.); Department of Biochemistry, Brown University, Providence, Rhode Island (P.-J.H.); Division of Biotechnology, Agricultural Research Institute, Wufeng, Taichung, Taiwan, Republic of China (J.-R.C.); School of Pharmacy, National Defense Medical Center, Taipei, Taiwan (W.-L.C.); Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan, Republic of China (S.-Z.L.); and Department of Pathology, China Medical University and Hospital, Taichung, Taiwan, Republic of China (H.-J.H.)

N-Butylidenephthalide (BP), isolated from the chloroform extract of Angelica sinensis, has been examined for its antitumor effects on glioblastoma multiforme brain tumors; however, little is known about its antitumor effects on hepatocellular carcinoma cells. Two hepatocellular carcinoma cell lines, HepG2 and J5, were treated with either N-butylidenephthalide or a vehicle, and cell viability and apoptosis were evaluated. Apoptosis-related mRNA and proteins expressed, including orphan receptor family Nurr1, NOR-1, and Nur77, were evaluated as well as the effect of N-butylidenephthalide in an in vivo xenograft model. N-Butylidenephthalide caused growth inhibition of both the cell lines at 25 µg/ml. Furthermore, N-butylidenephthalide-induced apoptosis seems to be related to Nur77 translocation from nucleus to cytosol, which leads to cytochrome c release and caspase-3-dependent apoptosis. N-Butylidenephthalide-related tumor apoptosis was associated with phosphatidylinositol 3-kinase/protein kinase B (AKT)/glycogen synthase kinase-3β rather than the mitogen-activated protein kinase or protein kinase C pathway. Blockade of AKT activation enhanced proliferation inhibition and the induction of phosphor-Bcl-2 and Nur77 proteins. Besides, the increasing apoptosis by BP via transfection wild-type cAMP-response element-binding protein (CREB) into tumor cell was suppressed by dominant phosphorylation site mutation of CREB. This finding suggested CREB pathway was also partly involved in tumor apoptosis caused by BP. Administration of N-butylidenephthalide showed similar antitumoral effects in both HepG2 and J5 xenograft tumors. N-Butylidenephthalide induced apoptosis in hepatocellular carcinoma cells, both in vitro and in vivo, suggesting a potential clinical use of this compound for improving the prognosis of hepatocellular carcinoma cells.

Address correspondence to: Dr. Horng-Jyh Harn, Department of Pathology, China Medical University and Hospital, 2, Yude Rd., North District, Taichung 40447, Taiwan, Republic of China. E-mail: dukeharn{at}www.cmuh.org.tw