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Selenium-containing thioredoxin reductase inhibitor ethaselen sensitizes non-small cell lung cancer to radiotherapy
Lei Wang1, Jia-Ning Fu, Jing-Yu Wang
1Peking University First Hospital, Beijing, China.
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.
Insights
Thioredoxin reductase (TR) drives non-small cell lung cancer (NSCLC) radioresistance. The novel TR inhibitor ethaselen (BBSKE) enhanced radiation efficacy in NSCLC cells and in vivo, showing promise for clinical treatment.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Thioredoxin reductase (TR) is implicated in non-small cell lung cancer (NSCLC) radioresistance.
- Mechanisms of TR's role in radioresistance are not fully understood.
- Ethaselen (BBSKE) is a novel organoselenium TR inhibitor in clinical trials.
Purpose of the Study:
- To investigate the radiosensitizing effect of BBSKE in NSCLC.
- To elucidate the role of TR in NSCLC radioresistance.
- To evaluate BBSKE's efficacy and toxicity in radiosensitizing NSCLC.
Main Methods:
- Assessed TR activity in A549 and H1299 cells post-irradiation.
- Pretreated cells with BBSKE to inhibit TR activity.
- Evaluated radiosensitizing effects of BBSKE in vitro and in vivo.
- Investigated BBSKE's effect on irradiation-induced NF-κB activation using reporter assays.
Main Results:
- TR activity significantly increased in NSCLC cells after radiation.
- BBSKE pretreatment inhibited radiation-induced TR activity.
- BBSKE enhanced radiation therapy efficacy both in vitro and in vivo.
- BBSKE suppressed irradiation-induced NF-κB activation.
- BBSKE demonstrated no observable toxicity.
Conclusions:
- TR plays a critical role in NSCLC radioresistance.
- BBSKE effectively inhibits TR and enhances radiation therapy.
- BBSKE is a potentially promising therapeutic agent for NSCLC patients.
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