title: Hh signaling inhibitors from Vitex negundo; naturally occurring inhibitors of the GLI1-DNA complex.
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.
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chiba 260-8675, Japan. midori_arai@chiba-u.jp
authors: Midori A
authors: MA
authors: Arai
authors: Teruhisa
authors: T
authors: Fujimatsu
authors: Kyoko
authors: K
authors: Uchida
authors: Samir K
authors: SK
authors: Sadhu
authors: Firoj
authors: F
authors: Ahmed
authors: Masami
authors: M
authors: Ishibashi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011485:Protein Binding / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism; D020950:Vitex / Q000737:chemistry*; D000071676:Zinc Finger Protein GLI1
chemical_list: D004224:Diterpenes; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D019253:Proto-Oncogene Proteins c-bcl-2; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C583772:nishindanol; D004247:DNA