RRC ID 71977
Author Arai MA, Tateno C, Koyano T, Kowithayakorn T, Kawabe S, Ishibashi M.
Title New hedgehog/GLI-signaling inhibitors from Adenium obesum.
Journal Org Biomol Chem
Abstract The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. We recently constructed a cell-based screening system to search for Hh/GLI signaling inhibitors from natural resources. Using our screening system, Adenium obesum was found to include Hh/GLI signaling inhibitors from our tropical plant extract libraries. Bioassay-guided fractionation of this plant extract led to the isolation of 17 cardiac glycosides (1-17), including 3 new compounds (4, 9, 16). These compounds showed strong inhibitory activities, especially the IC(50) of 17 is 0.11 μM. The inhibition of GLI-related protein expression with 3, 9, 11, 15 and 17 was observed in human pancreatic cancer cells (PANC1), which express Hh/GLI components aberrantly. The expressions of GLI-related proteins PTCH and BCL2 were clearly inhibited. These compounds also showed selective cytotoxicity against two cancer cell lines, with less effect against normal cells (C3H10T1/2). RT-PCT examinations showed that Ptch mRNA expression by 3, 11, 15 and 17 was inhibited.
Volume 9(4)
Pages 1133-9
Published 2011-2-21
DOI 10.1039/c0ob00677g
PMID 21170436
MeSH Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology Apocynaceae / chemistry* Cell Line, Tumor Cell Survival / drug effects Hedgehog Proteins / antagonists & inhibitors* Humans Molecular Structure Oncogene Proteins / antagonists & inhibitors* Oncogene Proteins / genetics Signal Transduction / drug effects* Structure-Activity Relationship Trans-Activators / antagonists & inhibitors* Trans-Activators / genetics Zinc Finger Protein GLI1
Human and Animal Cells 10T1/2(RCB0247) PANC-1(RCB2095)