Hh signaling inhibitors from Vitex negundo; Naturally occurring inhibitors of the GLI1-DNA complex

Midori A. Arai, Teruhisa Fujimatsu, Kyoko Uchida, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The hedgehog (Hh) signaling pathway has crucial roles in embryonic development, cell maintenance and proliferation, and is also known to contribute to cancer cell growth. New naturally occurring Hh inhibitors (1, 7 and 9) were isolated from Vitex negundo using our previously constructed cell-based assay. Bioactivity guided isolation provided 9 natural compounds including a new diterpene, nishindanol (9). Compounds 7 and 9 showed cytotoxicity against cancer cell lines in which Hh signaling was aberrantly activated. Vitetrifolin D (7; GLI1 transcriptional inhibition IC50 = 20.2 μM) showed inhibition of Hh related protein (PTCH and BCL2) production. Interestingly, the constructed electrophoresis mobility shift assay revealed that vitetrifolin D (7) disrupted GLI1 binding on its DNA binding domain. epi-Sclareol (8; inactive), possessing a similar structure to 7, did not show inhibition of GLI1-DNA complex formation. This is the first example of naturally occurring inhibitors of GLI1-DNA complex formation.

Original languageEnglish
Pages (from-to)1012-1018
Number of pages7
JournalMolecular BioSystems
Volume9
Issue number5
DOIs
Publication statusPublished - 2013 May 1
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Biology

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