Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
J Nat Prod. 2010 May 28;73(5):995-7. doi: 10.1021/np1000818.
Overexpression of glioma-associated oncogene 1 (GLI1), which has been characterized as a terminal effector and a target gene of the Hedgehog (Hh) signaling pathway, is associated with the development of cancer. A cellular screen was applied utilizing of a GLI-dependent luciferase reporter in human keratinocyte cells (HaCaT) and identified two terpenoids (1 and 2) and a flavonoid glycoside (5) from Acacia pennata as Hh/GLI inhibitors. Compounds 1, 2, and 5 exhibited selective cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells with no toxic effect on normal cells. This result was consistent with a dose-dependent reduction of the protein levels of antiapoptotic BCL-2 and the tumor suppressor patched 1 protein (PTCH). Additionally, treatment of 1 downregulated mRNA expression of Ptch in PANC1, suggesting that the compound has an inhibitory effect on the transcription of Hh/GLI.
Glioma-associated oncogene 1 (GLI1) 的过表达与癌症的发生有关，它已被确定为 Hedgehog (Hh) 信号通路的终末效应物和靶基因。利用人类角质形成细胞 (HaCaT) 中的 GLI 依赖性荧光素酶报告基因进行细胞筛选，从金合欢属植物中鉴定出两种萜类化合物 (1 和 2) 和一种类黄酮糖苷 (5) 作为 Hh/GLI 抑制剂。化合物 1、2 和 5 对人胰腺 (PANC1) 和前列腺 (DU145) 癌细胞表现出选择性细胞毒性，而对正常细胞没有毒性作用。这一结果与抗凋亡 BCL-2 和肿瘤抑制因子 patched 1 蛋白 (PTCH) 的蛋白水平呈剂量依赖性降低一致。此外，化合物 1 处理可下调 PANC1 中 Ptch 的 mRNA 表达，表明该化合物对 Hh/GLI 的转录具有抑制作用。
