Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription.
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 Bcl2 expression. 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.
Hosoya
Takahiro
T
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
Arai
Midori A
MA
Koyano
Takashi
T
Kowithayakorn
Thaworn
T
Ishibashi
Masami
M
D000818:Animals; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D000071676:Zinc Finger Protein GLI1
D001688:Biological Products; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D010936:Plant Extracts; D054852:Small Molecule Libraries; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1