Article ID Journal Published Year Pages File Type
1395613 European Journal of Medicinal Chemistry 2014 8 Pages PDF
Abstract

•Selenadiazoles are identified as radiosensitizers for the first time.•Selenadiazoles act as effective TrxR inhibitor.•Selenadiazoles sensitize cancer cells to X-ray via ROS-mediated signaling.

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.

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Related Topics
Physical Sciences and Engineering Chemistry Organic Chemistry
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