Radiotherapy is an essential and effective treatment modality for cancer. Excessive levels of reactive oxygen species (ROS) induced by ionizing radiation disrupt the redox homeostasis and lead to oxidative stress that may result in cell death. However, the tumor cell microenvironment is dynamic and responds to radiotherapy by activating numerous cellular signaling pathways. By scavenging excess ROS, the activity levels of the endogenous antioxidant enzymes result in radioresistance and worsen the clinical outcomes. To assess the full potential of radiotherapy, it is essential to explore the underlying mechanisms of oxidative stress in radiotherapy for potential target identification. The present review article summarized recent data demonstrating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) as a powerful transcription factor and one of the major cellular defense mechanisms that protect against oxidative stress in response to radiotherapy; the glutathione (GSH) and thioredoxin (Trx) systems complement each other and are effective antioxidant mechanisms associated with the protection of cancer cells from radiation damage. In addition, it is suggested that dual targeting to inhibit GSH and Trx enzymes may be a potential strategy for the development of radiosensitive and radioprotective drugs.

Radiotherapy is one of the most important treatments for breast cancer. Ferroptosis is a recently recognized form of regulated cell death that is characterized by lipid peroxidation. However, whether ionizing radiation (IR) could induce ferroptosis in breast cancer and how it works remain unknown. Bioinformatics analysis were performed to screen ferroptosis-related genes differentially expressed in breast tumor tissue and normal tissue. Then, breast cancer cell lines with different estrogen receptor (ER) phenotypes were used for studies in vitro, including ER-positive (MCF-7 and ZR-75-1) and ER-negative (MDA-MB-231) cells. The dynamic changes of mRNA and protein levels were examined after x-ray of 8 Gy by qRT-PCR and Western blotting, respectively. Immunoprecipitation (IP) was used to explore the interaction between proteins. Luciferase assay was used to analyze the transcriptional regulation effect of ESR1 on SLC7A11. BODIPY C11 and trypan blue dyes were used to determine lipid peroxidation and cell death, respectively. The result showed that the ferroptosis-related gene SLC7A11 was higher in breast cancer tissues compared with normal tissues and associated with poor survival. A positive correlation exists between ESR1 and SLC7A11 expression. ESR1 promoted SLC7A11 expression at the early stage after IR. ESR1/SLC7A11 knockdown significantly enhanced IR-induced ferroptosis in ER-positive cells. At 12 h after IR, the IP data showed the interaction between E3 ubiquitin ligase NEDD4L and SLC7A11 increased, followed by the ubiquitylation and degradation of SLC7A11. Thus, SLC7A11 expression was regulated by both ESR1 and NEDD4L, in opposite ways. For the first time, we elucidated that ESR1 and NEDD4L functioned together after radiation treatment and finally induced ferroptosis in breast cancer cells, which provides novel insight into the guidance of clinical treatment of breast cancer.

A series of physiological and pathological changes occur after radiotherapy and accidental exposure to ionizing radiation (IR). These changes cause serious damage to human tissues and can lead to death. Radioprotective countermeasures are radioprotective agents that prevent and reduce IR injury or have therapeutic effects. Based on a good understanding of radiobiology, a number of protective agents have achieved positive results in early clinical trials. The present review grouped known radioprotective agents according to biochemical categories and potential clinical use, and reviewed radiation countermeasures, i.e., radioprotectors, radiation mitigators and radiotherapeutic agents, with an emphasis on their current status and research progress. The aim of the present review is to facilitate the selection and application of suitable radioprotectors for clinicians and researchers, to prevent or reduce IR injury.