title: Selenadiazole derivatives as potent thioredoxin reductase inhibitors that enhance the radiosensitivity of cancer cells.
abstract: Thioredoxin system is an attractive target to overcome radioresistance in cancer therapy. The redox enzyme thioredoxin reductase (TrxR) plays a vital role in restoring cellular thiol redox balance disrupted by radiation-induced reactive oxygens species (ROS) generation and oxidative damage. In this study, a series of 1,2,5-selenadiazoles have been synthesized and identified as highly effective inhibitors of TrxR to disrupt the intracellular redox balance, and thus significantly enhanced the sensitivity of cancer cells to X-ray. Upon irradiation, 1,2,5-selenadiazoles displayed a marked synergistic inhibitory effect on radioresistant A375 melanoma cell through enhancement of ROS overproduction, and subsequent induction of ROS-promoted apoptotic pathways, which triggered then mitochondrial dysfunction and caspase activation, finally resulted in augment of radiotherapeutic efficacy. Interestingly, we also found the interaction sites between 1,2,5-selenadiazole and the model peptide of TrxR, which can be confirmed by MALDI-ToF-MS. These results clearly demonstrate TrxR as a potential target for therapy of radioresistant cancers, and selenadiazole derivatives may be attractive radiosensitizing agent by targeting TrxR.
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Yuan-Wei
authors.initials: YW
authors.lastname: Liang
authors.affiliation: The Third Affiliated Hospital of Sun-Yat-Sen University, Guangzhou 510632, China.
authors.forename: Junsheng
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China. Electronic address: tchentf@jnu.edu.cn.
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005720:Gamma Rays; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D001393:Azoles; D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D013880:Thioredoxin-Disulfide Reductase
keywords: ROS; Radiosensitization; Selenadiazole; Thioredoxin reductase