Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
Bioorg Med Chem Lett. 2011 Jan 15;21(2):718-22. doi: 10.1016/j.bmcl.2010.11.126. Epub 2010 Dec 5.
The inhibition of the Hedgehog (Hh) signaling pathway has emerged as an anti-cancer strategy. Three flavonoid glycosides including 2 new compounds (1-2) were isolated from Excoecaria agallocha as Hedgehog/GLI1-mediated transcriptional inhibitors and exhibited cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells. Our data revealed that compound 1 clearly inhibited the expression of GLI-related proteins (PTCH and BCL-2) and blocked the translocation of GLI1 transcription factors into the nucleus in PANC1. Deleting the Smoothened (Smo) function in PANC1 treated with 1 led to downregulation of the mRNA expression of Ptch. This study describes the first Hh signaling inhibitor which blocks GLI1 movement into the nucleus without interfering with Smo.
Hedgehog（Hh）信号通路的抑制已成为一种抗癌策略。从 Excoecaria agallocha 中分离出三种类黄酮糖苷，包括两种新化合物（1-2），它们是 Hedgehog/GLI1 介导的转录抑制剂，对人胰腺（PANC1）和前列腺（DU145）癌细胞具有细胞毒性。我们的数据表明，化合物 1 明显抑制了 GLI 相关蛋白（PTCH 和 BCL-2）的表达，并阻止了 GLI1 转录因子在 PANC1 中的核转位。在用 1 处理的 PANC1 中删除 Smoothened（Smo）功能会导致 Ptch 的 mRNA 表达下调。这项研究描述了第一个 Hh 信号抑制剂，它可以阻止 GLI1 进入细胞核，而不干扰 Smo。
