title: Clionosterol and ethyl cholestan-22-enol isolated from the rhizome of Polygala tenuifolia inhibit phosphatidylinositol 3-kinase/Akt pathway.
abstract: Phosphatidylinositol 3-kinase (PI3K)/Akt inhibitors were isolated from the rhizome of Polygala tenuifolia WILLD (PT, Polygalaceae), which has been used in traditional Chinese medicine for inflammation, dementia, amnesia, neurasthenia and cancer, by activity-guided fractionation. For the assay of PI3K/Akt pathway, cytoprotective Tat-transduced CHME5 cells, which are the cytoprotective phenotype against lypopolysaccharide (LPS)/cycloheximide (CHX), were used. We isolated 4 anti-cytoprotective compounds, clionasterol (1), ethyl cholestan-22-enol (2), 3-O-β-D-glucosyl ethyl cholestan-22-enol (3), and 3-O-β-D-glucopyranosyl clionasterol (4) from EtOAc fraction of PT against Tat-transduced CHME5 cells. Of them, (1) and (2) most potently abolished cytoprotective effect of Tat-transduced CHME5 cells. These constituents (1) and (2) inhibited the activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and its downstream molecules, Akt/glycogen synthase kinase (GSK)3β, in PI3K/Akt cell survival signaling pathway, but did not suppress the activation of PI3K. Based on these finding, (1) and (2) may abolish the cytoprotective phenotype of Tat-transduced CHME5 cells by inhibiting PDK1 phosphorylation in PI3K/Akt pathway.
authors.affiliation: Department of Life and Nanopharmaceutical Sciences and Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130–701, Korea.
authors.forename: Thi Kim Van
authors.initials: TK
authors.lastname: Le
authors.forename: Jin Ju
authors.initials: JJ
authors.lastname: Jeong
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
mesh_terms: D002460:Cell Line; D002777:Cholestanols / Q000302:isolation & purification / Q000494:pharmacology*; D003513:Cycloheximide; D019610:Cytoprotection / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015696:Gene Products, tat / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D031801:Polygala / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D027343:Rhizome / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D012855:Sitosterols / Q000302:isolation & purification / Q000494:pharmacology*; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D002777:Cholestanols; D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D008070:Lipopolysaccharides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010936:Plant Extracts; D012855:Sitosterols; D014764:Viral Proteins; C025473:gamma-sitosterol; D003513:Cycloheximide; D051057:Proto-Oncogene Proteins c-akt