title: Selenium-containing thioredoxin reductase inhibitor ethaselen sensitizes non-small cell lung cancer to radiotherapy.
abstract: It has been proposed that thioredoxin reductase (TR) is a mediator that allows non-small cell lung cancer (NSCLC) to develop resistance to irradiation; however, little is known regarding the detailed mechanisms of action. Thus, ethaselen {1, 2-[bis (1,2-benzisoselenazolone-3 (2H)-ketone)] ethane, BBSKE}, a novel organoselenium TR inhibitor, is currently being investigated in a phase I clinical trial in China. However, its radiosensitizing effect remains unexplored. In this study, we found that the activity of TR increased dramatically in both A549 and H1299 cells after radiation, and moreover, could be inhibited by pretreatment with BBSKE (5 μmol/l). As a TR inhibitor, BBSKE enhanced the efficacy of radiation therapy both in vivo and in vitro without observable toxicity. BBSKE was found to suppress irradiation-induced NF-κB activation dramatically when using A549 cells stably transfected with NF-κB luciferase reporter. These results show the critical role of TR in the radioresistance of NSCLC and suggest that BBSKE is a potentially promising agent for the treatment of patients with NSCLC clinically.
authors.affiliation: Peking University First Hospital, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Fu
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Wang
authors.forename: Cun-Jing
authors.initials: CJ
authors.lastname: Jin
authors.forename: Xiao-Yuan
authors.initials: XY
authors.lastname: Ren
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tan
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Han-Wei
authors.initials: HW
authors.lastname: Yin
authors.forename: Kun
authors.initials: K
authors.lastname: Xiong
authors.forename: Tian-Yu
authors.initials: TY
authors.lastname: Wang
authors.forename: Xin-Min
authors.initials: XM
authors.lastname: Liu
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Zeng
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology* / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D016566:Organoselenium Compounds / Q000494:pharmacology* / Q000633:toxicity; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000633:toxicity; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors; D014162:Transfection
chemical_list: C478160:(1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone))ethane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016328:NF-kappa B; D016566:Organoselenium Compounds; D011838:Radiation-Sensitizing Agents; D008156:Luciferases; D013880:Thioredoxin-Disulfide Reductase