Reference - Detail
RRC ID | 43308 |
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Author | Hosoya T, Arai MA, Koyano T, Kowithayakorn T, Ishibashi M. |
Title | Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription. |
Journal | Chembiochem |
Abstract |
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. |
Volume | 9(7) |
Pages | 1082-92 |
Published | 2008-5-5 |
DOI | 10.1002/cbic.200700511 |
PMID | 18357592 |
MeSH | Animals Biological Products / chemistry* Biological Products / pharmacology* Cell Line, Tumor Drug Evaluation, Preclinical Gene Expression Regulation, Neoplastic / drug effects Hedgehog Proteins / antagonists & inhibitors* Hedgehog Proteins / metabolism Humans Inhibitory Concentration 50 Oncogene Proteins / antagonists & inhibitors* Oncogene Proteins / metabolism Plant Extracts / chemistry Plant Extracts / pharmacology Signal Transduction / drug effects Small Molecule Libraries / pharmacology* Trans-Activators / antagonists & inhibitors* Trans-Activators / metabolism Transcription, Genetic / drug effects* Transcriptional Activation / drug effects Zinc Finger Protein GLI1 |
IF | 2.576 |
Times Cited | 100 |
WOS Category | CHEMISTRY, MEDICINAL BIOCHEMISTRY & MOLECULAR BIOLOGY |
Resource | |
Human and Animal Cells | 10T1/2(RCB0247) PANC-1(RCB2095) |