Naturally occurring small-molecule inhibitors of Hedgehog/GLI-mediated transcription

Takahiro Hosoya, Midori A. Arai, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

Research output: Contribution to journalArticlepeer-review

118 Citations (Scopus)


The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. To search for Hh/GLI inhibitors, we screened for naturally occurring inhibitors of the transcriptional activator GLI1 by using a cell-based assay. We identified zerumbone (1), zerumbone epoxide (2), staurosporinone (9), 6-hydroxystaurosporinone (10), arcyriaflavin C (11) and 5,6-dihydroxyarcyriaflavin A (12) as inhibitors of GLI-mediated transcription. In addition, we isolated physalins F (17) and B (18) from Physalis minima, which are also potent inhibitors. These compounds also inhibited GLI2-mediated transactivation. Semiquantitative RT-PCR and Western blotting analysis further revealed that 1, 9, 17, and 18 decreased Hh-related component expressions. We also show that inhibitors of GLI-mediated transactivation reduce the level of the antiapoptosis Bcl2expression. Finally, these identified compounds were cytotoxic to PANC1 pancreatic cancer cells, which express Hh/GLI components. These results strongly suggest that the cytotoxicity of the compounds to PANC1 cells correlates with their inhibition of GLI-mediated transcription.

Original languageEnglish
Pages (from-to)1082-1092
Number of pages11
Issue number7
Publication statusPublished - 2008 May 5
Externally publishedYes


  • GLI
  • Hedgehog
  • Inhibitors
  • Natural products

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry


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