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

Abstract

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 g/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-3␤ 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.Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide. The main curative therapies for cancer are surgery and radiation, which, in general, are only successful if the cancer is diagnosed at an early stage. CurThis work was supported National Science Council of the Republic of China

Traditional Chinese medicine for prevention and treatment of hepatocarcinoma: From bench to bedside

“…20(R)ginsenoside Rg3, a component from Panax ginseng, may upregulate TNFα and induce apoptosis in induced liver tumors in SD rats [105] . Blood tonifying herb or component, including Di Huang (Rehmannia glutinosa) and Nbutylidenephthalide from DangGui (Angelica sinensis), is effective to induce apoptosis of hepatocarcinoma cells [106,107] . GouQi (Lycium barbarum), a liverYin tonifying herb, is effective to inhibit proliferation and stimulate p53mediated apoptosis in liver cancer cells [106] .…”

Developing New Small Molecular Drugs for Prostate Cancer Therapy

“…Butylidenephthalide (BP), isolated from Angelica sinensis, showed a dramatic therapeutic effect in against glioblastoma multiforme and its derivative also inhibit cell growth in hepatocellular carcinoma and lung adenocarcinoma cells [61][62][63]. Furthermore, butylidenephthalide could inhibit cell proliferation and induce cell death in human prostate cancer cells (PC-3 and LNCaP) [31].…”

Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

“…1 BP induces Nur77-mediated apoptosis via the protein kinase C/JNK pathway. 4,7,9,10 BP downregulates the expression of S-phase kinase-associated protein (Skp2), which leads to an increase in p16 and p21 expression, causing G 0 /G 1 arrest. 2 BP inhibits telomerase activity by repressing hTERT transcriptional activity via the downregulation of Sp1 or AP-2 expression.…”

“…9 In particular, BP has been developed to treat brain tumors due to its ability to permeate through the blood-brain barrier and enter into the brain. 1 BP induces Nur77-mediated apoptosis via the protein kinase C/JNK pathway.…”