title: Terpenoids and a flavonoid glycoside from Acacia pennata leaves as hedgehog/GLI-mediated transcriptional inhibitors.
abstract: Overexpression of glioma-associated oncogene 1 (GLI1), which has been characterized as a terminal effector and a target gene of the Hedgehog (Hh) signaling pathway, is associated with the development of cancer. A cellular screen was applied utilizing of a GLI-dependent luciferase reporter in human keratinocyte cells (HaCaT) and identified two terpenoids (1 and 2) and a flavonoid glycoside (5) from Acacia pennata as Hh/GLI inhibitors. Compounds 1, 2, and 5 exhibited selective cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells with no toxic effect on normal cells. This result was consistent with a dose-dependent reduction of the protein levels of antiapoptotic BCL-2 and the tumor suppressor patched 1 protein (PTCH). Additionally, treatment of 1 downregulated mRNA expression of Ptch in PANC1, suggesting that the compound has an inhibitory effect on the transcription of Hh/GLI.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
authors.forename: Yusnita
authors.initials: Y
authors.lastname: Rifai
authors.forename: Midori A
authors.initials: MA
authors.lastname: Arai
authors.forename: Takashi
authors.initials: T
authors.lastname: Koyano
authors.forename: Thaworn
authors.initials: T
authors.lastname: Kowithayakorn
authors.forename: Masami
authors.initials: M
authors.lastname: Ishibashi
mesh_terms: D000045:Acacia / Q000737:chemistry*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001483:Base Sequence; D004354:Drug Screening Assays, Antitumor; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D053823:Hedgehog Proteins / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018515:Plant Leaves / Q000737:chemistry; D011794:Quercetin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015398:Signal Transduction; D013729:Terpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D013785:Thailand; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics; D000071676:Zinc Finger Protein GLI1
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C400551:GLI1 protein, human; D006027:Glycosides; D053823:Hedgehog Proteins; D013729:Terpenes; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C550049:drim-8-ene; C550050:quercetin 3-O-beta-D-glucopyranosyl-4-O-beta-D-glucopyranoside; C550051:taepeenin D; D011794:Quercetin