title: New Hedgehog/GLI signaling inhibitors from Excoecaria agallocha.
abstract: The inhibition of the Hedgehog (Hh) signaling pathway has emerged as an anti-cancer strategy. Three flavonoid glycosides including 2 new compounds (1-2) were isolated from Excoecaria agallocha as Hedgehog/GLI1-mediated transcriptional inhibitors and exhibited cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells. Our data revealed that compound 1 clearly inhibited the expression of GLI-related proteins (PTCH and BCL-2) and blocked the translocation of GLI1 transcription factors into the nucleus in PANC1. Deleting the Smoothened (Smo) function in PANC1 treated with 1 led to downregulation of the mRNA expression of Ptch. This study describes the first Hh signaling inhibitor which blocks GLI1 movement into the nucleus without interfering with Smo.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 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: Samir K
authors.initials: SK
authors.lastname: Sadhu
authors.forename: Firoj
authors.initials: F
authors.lastname: Ahmed
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; D002470:Cell Survival / Q000187:drug effects; D019665:Euphorbiaceae / Q000737:chemistry*; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D000071676:Zinc Finger Protein GLI1
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; C400551:GLI1 protein, human; D006027:Glycosides; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1