title: New hedgehog/GLI-signaling inhibitors from Adenium obesum.
abstract: The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. We recently constructed a cell-based screening system to search for Hh/GLI signaling inhibitors from natural resources. Using our screening system, Adenium obesum was found to include Hh/GLI signaling inhibitors from our tropical plant extract libraries. Bioassay-guided fractionation of this plant extract led to the isolation of 17 cardiac glycosides (1-17), including 3 new compounds (4, 9, 16). These compounds showed strong inhibitory activities, especially the IC(50) of 17 is 0.11 μM. The inhibition of GLI-related protein expression with 3, 9, 11, 15 and 17 was observed in human pancreatic cancer cells (PANC1), which express Hh/GLI components aberrantly. The expressions of GLI-related proteins PTCH and BCL2 were clearly inhibited. These compounds also showed selective cytotoxicity against two cancer cell lines, with less effect against normal cells (C3H10T1/2). RT-PCT examinations showed that Ptch mRNA expression by 3, 11, 15 and 17 was inhibited.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. marai@p.chiba-u.ac.jp
authors.forename: Midori A
authors.initials: MA
authors.lastname: Arai
authors.forename: Chikashi
authors.initials: C
authors.lastname: Tateno
authors.forename: Takashi
authors.initials: T
authors.lastname: Koyano
authors.forename: Thaworn
authors.initials: T
authors.lastname: Kowithayakorn
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kawabe
authors.forename: Masami
authors.initials: M
authors.lastname: Ishibashi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D029062:Apocynaceae / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics; D000071676:Zinc Finger Protein GLI1
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1