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: Yuan-Wei Liang, Junsheng Zheng, Xiaoling Li, Wenjie Zheng, Tianfeng Chen
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 84 Pg. 335-42 (Sep 12 2014) ISSN: 1768-3254 [Electronic] France
• PMID: 25036792 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• Azoles
• Enzyme Inhibitors
• Organoselenium Compounds
• Radiation-Sensitizing Agents
• Reactive Oxygen Species
• Thioredoxin-Disulfide Reductase

Topics

• Apoptosis (drug effects)
• Azoles (chemical synthesis, chemistry, pharmacology)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Gamma Rays
• Humans
• Molecular Structure
• Neoplasms (drug therapy, enzymology, pathology, radiotherapy)
• Organoselenium Compounds (chemical synthesis, chemistry, pharmacology)
• Radiation Tolerance (drug effects)
• Radiation-Sensitizing Agents (chemical synthesis, chemistry, pharmacology)
• Reactive Oxygen Species (metabolism)
• Structure-Activity Relationship
• Thioredoxin-Disulfide Reductase (antagonists & inhibitors, metabolism)
• Tumor Cells, Cultured