New Hedgehog/GLI signaling inhibitors from Excoecaria agallocha

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.

Graphical abstractHedgehog/GLI1-mediated transcriptional inhibitors (1, 2, and 8) were isolated and their cytotoxicity against cancer cells were described. Treatment with 1 led to a significant decrease in the level of nuclear GLI1 protein and Ptch mRNA expression of PANC1 in an Smo-independent manner.Figure optionsDownload full-size imageDownload as PowerPoint slide