title: Hedgehog inhibitors from Withania somnifera.
abstract: The hedgehog (Hh) signaling pathway performs an important role in embryonic development and in cellular proliferation and differentiation. However, aberrant activation of the Hh signaling pathway is associated with tumorigenesis. Hh signal inhibition was evaluated using a cell-based assay system that targets GLI1-mediated transcription. Activity-guided isolation of the Withania somnifera MeOH extract led to the isolation of six compounds: withaferin A (1) and its derivatives (2-6). Compounds 1 and 2 showed strong inhibition of Hh/GLI1-mediated transcriptional activity with IC50 values of 0.5 and 0.6 μM, respectively. Compounds 1, 2, 3, and 6 were cytotoxic toward human pancreatic (PANC-1), prostate (DU145) and breast (MCF7) cancer cells. Furthermore, 1 also inhibited GLI1-DNA complex formation in EMSA.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Yoneyama
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan. Electronic address: midori_arai@chiba-u.jp.
authors.forename: Midori A
authors.initials: MA
authors.lastname: Arai
authors.affiliation: Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh.
authors.forename: Samir K
authors.initials: SK
authors.lastname: Sadhu
authors.affiliation: Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka 1000, Bangladesh.
authors.forename: Firoj
authors.initials: F
authors.lastname: Ahmed
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan. Electronic address: mish@chiba-u.jp.
authors.forename: Masami
authors.initials: M
authors.lastname: Ishibashi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D032341:Withania / Q000737:chemistry*; D054358:Withanolides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053823:Hedgehog Proteins; D054358:Withanolides; C009684:withaferin A
keywords: Hedgehog signaling pathway; Inhibitor; Natural product; Withania somnifera