In conclusion, PCH4, a derivative of BP, induced Nur77-mediated apoptosis via the JNK pathway and this mechanism, which is different from that of BP, may explain the increase in the anti-tumor effects on GBM.

This investigation was designed to determine the inhibitory effects and mechanisms of n-butylidenephthalide (BP) from Angelica sinensis on smooth muscle cell (SMC) proliferation in vitro and in balloon injured rat carotid artery. Treatment of cultured rat aorta SMC-derived A7r5 cells with 25-100 μg/mL BP significantly inhibited the proliferation and arrested the cell cycle in G(0)/G(1) phase. BP induced the expression and migration of Nur77 from the nucleus to the cytoplasm. Among signal pathways, JNK and p38 MAPK were phosphorylated after BP treatment. In vivo, the neointimal area of common carotid artery 2 weeks after balloon injury reduced significantly in Sprague-Dawley rats treated with 150-300 mg/kg BP compared with the control. The proliferative activity indicated by immunohistochemical detection of Ki-67 positive cells in the neointima was significantly decreased in the 60-300 mg/kg BP treatment groups. The apoptotic activity indicated by cleaved caspase-3 positive cells and Nur77 positive cells in the neointima was significantly increased in rats treated with 60-300 mg/kg BP. This study demonstrated BP inhibited neointimal hyperplasia in balloon injured rat carotid artery due to its dual effects of proliferative inhibition and apoptotic induction on SMCs. Up-regulation of Nur77 gene may partly explain the antihyperplasia activity of BP on the neointima.

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N-butylidenephthalide(BP), a nature compound from Angelica sinensis, has the antitumor effect in vitro and in vivo. Further, we modified the chemical structure of BP for increasing the antitumor effect and one derivative is (Z)-N-(2-(dimethylamino)ethyl)-2-(3-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenoxy)acetamide, PCH4, has 4 times tumor inhibition on human glioblastoma multiform DBTRG-05MG cells. The IC50 of PCH4 on DBTRG-05MG cells is 50 μg/ml. The PCH4 induced apoptosis was related to Nur77 expression and translocation from nucleus to cytosol. Furthermore, the inhibition of PCH4-induced Nur77 expression by Nur77 siRNA can reduce the PCH4-induced apoptosis. In addition, The PCH4-induced apoptosis was associated with JNK pathway. The JNK inhibitor, SP600125, inhibited the Nur77 mRNA expression and reduced the PCH4-induced apoptosis. In conclusion, It suggesting us that the PCH4, the derivatives of BP, induce the Nur77-mediated apoptosis through the JNK pathway and this mechanism different from BP may increase the antitumor effect on GBM cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 770.