期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 17, 页码 3541-3544出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.06.081
关键词
Hedgehog signaling pathway; Inhibitor; Natural product; Withania somnifera
资金
- JSPS [26305001, 26293022, 25670045]
- MEXT [23102008]
- Grants-in-Aid for Scientific Research [25670045, 23102008, 15H04650, 26293022, 26305001] Funding Source: KAKEN
The hedgehog (Hh) signaling pathway performs an important role in embryonic development and in cellular proliferation and differentiation. However, aberrant activation of the Hh signaling pathway is associated with tumorigenesis. Hh signal inhibition was evaluated using a cell-based assay system that targets GLI1-mediated transcription. Activity-guided isolation of the Withania somnifera MeOH extract led to the isolation of six compounds: withaferin A (1) and its derivatives (2-6). Compounds 1 and 2 showed strong inhibition of Hh/GLI1-mediated transcriptional activity with IC50 values of 0.5 and 0.6 mu M, respectively. Compounds 1, 2, 3, and 6 were cytotoxic toward human pancreatic (PANC-1), prostate (DU145) and breast (MCF7) cancer cells. Furthermore, 1 also inhibited GLI1-DNA complex formation in EMSA. (C) 2015 Elsevier Ltd. All rights reserved.
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