title: Dioscin, a natural steroid saponin, induces apoptosis and DNA damage through reactive oxygen species: a potential new drug for treatment of glioblastoma multiforme.
abstract: Dioscin, a natural product obtained from medicinal plants shows lipid-lowering, anti-cancer and hepatoprotective effects. However, the effect of it on glioblastoma is unclear. In this study, dioscin significantly inhibited proliferation of C6 glioma cells and caused reactive oxygen species (ROS) generation and Ca²⁺ release. ROS accumulation affected levels of malondialdehyde, nitric oxide, glutathione disulfide and glutathione, and caused cell apoptosis. In addition, ROS generation caused mitochondrial damage including structural changes, increased mitochondrial permeability transition and decreased mitochondria membrane potential, which led to the release of cytochrome C, nuclear translation of programmed cell death-5 and increased activities of caspase-3,9. Simultaneously, dioscin down-regulated protein expression of Bcl-2, Bcl-xl, up-regulated expression of Bak, Bax, Bid and cleaved poly (ADP-ribose) polymerase. Also, oxygen stress induced S-phase arrest of cancer cells by way of regulating expression of DNA Topo I, p53, CDK2 and Cyclin A and caused DNA damage. In a rat allograft model, dioscin significantly inhibited tumor size and extended the life cycle of the rats. In conclusion, dioscin shows noteworthy anti-cancer activity on glioblastoma cells by promoting ROS accumulation, inducing DNA damage and activating mitochondrial signal pathways. Ultimately, we believe dioscin has promise as a new therapy for the treatment of glioblastoma.
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Lv
authors.forename: Lingli
authors.initials: L
authors.lastname: Zheng
authors.forename: Deshi
authors.initials: D
authors.lastname: Dong
authors.forename: Lina
authors.initials: L
authors.lastname: Xu
authors.forename: Lianhong
authors.initials: L
authors.lastname: Yin
authors.forename: Youwei
authors.initials: Y
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Qi
authors.forename: Xu
authors.initials: X
authors.lastname: Han
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009368:Neoplasm Transplantation; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism*; D012503:Saponins / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D012503:Saponins; C019357:dioscin; D004144:Diosgenin
keywords: 2-(6-Amino-3-imino-3H-xanthen-9-yl) benzoic acid methyl ester; 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide; 4′6′-diamidino-2-phenyl-indole; AO/EB; Apoptosis; C6 glioma cells; CDK2; DAPI; DNA Topo I; DNA Topoismerase I; DNA damage; Dioscin; ECL; FBS; GSH; GSSG; HE; Hematoxylin and Eosin; MDA; MPT; MRI; MTG; MTT; Magnetic Resonance Imaging; MitoTracker Green-FM; Mitochondrial pathways; NO; PARP; PDCD5; PMSF; ROS; Rh123; SDS-PAGE; TEM; TUNEL; TdT-mediated dUTP Nick-End Labeling; acridine orange/ethidium bromide; cyclin-dependent kinase 2; enhanced chemiluminescence; fetal bovine serum; glutathione; glutathione disulfide; malondialdehyde; mitochondria membrane potential; mitochondrial permeability transition; nitric oxide; p-nitroaniline; pNA; phenylmethanesulfonyl fluoride; poly (ADP-ribose) polymerase; programmed cell death-5; reactive oxygen species; sodium dodecyl sulfate polyacrylamide gel electrophoresis; transmission electron microscope; ΔΨm