Enhancing Tumour Radiosensitivity by Targeting NRF2 Antioxidant System

The challenge of radioresistance (RR) in radiotherapy (RT) is currently being tackled, on one hand, by introducing into clinical practice new RT equipment with high quality of ionizing beams, high precision of radiation delivery to tumour, and optimization of treatment plans. On the other hand, new therapeutic methods for suppressing RR in tumours of cancer patients are being developed through a combination of RT with chemo-, immuno- and targeted therapies based on molecular diagnostic data. As a result of numerous preclinical and clinical trials of the combination therapy, the main molecular mechanisms, driving an increase in radiosensitivity (RS), were found out, and the key cellular signalling pathways responsible for RR were established. One of the established mechanisms is in adaptation of cancer cells to an elevated level of reactive oxygen species (ROS) by activation of antioxidant systems (AOS) of cellular protection and survival. Considering that RT relies mainly on the production of ROS that damage DNA and cause cancer cell death. Consequently, the activation of the AOS can mitigate the RT effectiveness, and it is assumed that suppression of the AOS and cellular adaptation mechanisms to a high ROS level can increase tumour RS and enhance the effectiveness of radiotherapy. In this review we discussed a role of one of the key components of the cellular AOS being under the control by a transcription factor NRF2 (nuclear erythroid factor 2) which governs the expression of a battery of antioxidant enzymes and protects cells from oxidative stress induced by RT. First, we briefly discussed the molecular function of the redox-sensitive the NRF2 AOS, which is activated in cells following the increased ROS level due to irradiation. Second, we reviewed the experimental and clinical data on activation of the NRF2 AOS in some cancer cells and tumour under ionizing irradiation. Third, we discussed results of numerous experimental and clinical investigations which clearly showed that suppression of the NRF2 AOS leads to an increase in radiosensitivity of various cancers and an enhancement in the effectiveness of RT in cancer patients. These data confirm the potential of combining RT with targeted therapy aiming at the suppression of the NRF2 cytoprotective AOS. Based on multiple experimental and clinical studies, we advocated a role of NRF2 inhibitors as radiosensitizers that promote overcoming radioresistance due to extra ROS accumulation and oxidative stress induction by inhibition of the NRF2-dependent antioxidant responses to radiotherapy.