title: Icaritin Sensitizes Human Glioblastoma Cells to TRAIL-Induced Apoptosis.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered to be one of the most promising candidates in research on treatments for cancer, because it induces apoptosis in a wide variety of cancer cells but not in most normal human cell types. However, many cells including glioblastoma (GBM) cells are resistant to TRAIL-induced apoptosis, which limits the potential application of TRAIL in cancer therapy. Icaritin, a hydrolytic product of icariin from Epimedium Genus, has been identified as a potential therapeutic and preventive agent in renal cell carcinoma and breast cancer. In this study, we investigated whether Icaritin treatment could modulate TRAIL-induced apoptosis in GBM. The effect of icaritin on TRAIL sensitivity was assessed in human GBM U87 and U373 cells. The underlying regulatory cascades were approached by biochemical and pharmacological strategies. We found that nontoxic concentration of icaritin alone had no significant effect on the level of apoptosis, but a combination treatment of TRAIL and icaritin caused a significantly more profound apoptosis. The sensitization was accompanied by c-FLIP down-regulation and inhibition of NF-κB activity. Studies have further demonstrated that silencing NF-κB alone was sufficient to down-regulate c-FLIP expression and sensitized both tested cells to TRAIL-induced apoptosis. These data suggest that icaritin sensitizes TRAIL-induced tumor cell apoptosis via suppression of NF-κB-dependent c-FLIP expression, providing in vitro evidence supporting the notion that icaritin is a potential sensitizer of TRAIL in anticancer therapy against human GBM.
authors.affiliation: Department of Neurology, Qilu Hospital of Shandong University, Jinan, Shandong, China.|Department of Neurology, Linyi People's Hospital, Linyi, Shandong, China.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Neurology, Provincial Hospital of Shandong University, Jinan, Shandong, China.|Department of Neurology, The Second Affiliated Hospital, Medical College of Qingdao University, Qingdao, Shandong, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, Huangdao Traditional Chinese Medicine Hospital, Qingdao, Shandong, China.
authors.forename: Pengzhi
authors.initials: P
authors.lastname: Hou
authors.affiliation: Department of Radiology, Qingdao Hiser Medical Center, Qingdao, Shandong, China.|Department of Radiology, Provincial Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Chuanwu
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Neurosurgery, Qingdao Hiser Medical Center, Qingdao, Shandong, China.
authors.forename: Longxi
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Neurology, Qingdao Hiser Medical Center, Qingdao, Shandong, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Tang
authors.affiliation: Department of Neurology, Qingdao Hiser Medical Center, Qingdao, Shandong, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Qingdao Hiser Medical Center, Qingdao, Shandong, China.
authors.forename: Yunxu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Qingdao Hiser Medical Center, Qingdao, Shandong, China. dryongjiliu@163.com.
authors.forename: Yongji
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005419:Flavonoids / Q000494:pharmacology*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D005419:Flavonoids; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C499403:icaritin
keywords: GBM; Icaritin; NF-κB; TRAIL; c-FLIP