Enhancing Tumour Radiosensitivity by Targeting NRF2 Antioxidant System

The challenge of radioresistance in radiotherapy is currently tackled by introducing new radiotherapy facilities with high-quality of ionizing beams, high-precision of radiation delivery to tumour, and optimized treatment plans. This strategy is further enhanced by the development of new therapeutic methods for suppressing radioresistance in tumours of cancer patients by combining radiotherapy with chemo-, immuno-, and targeted therapies tailored to patients’ molecular profiles. As a result of numerous preclinical and clinical trials of the combination therapy, the primary molecular mechanisms, driving an increase in radiosensitivity, and the key cellular signalling pathways responsible for radioresistance were identified. One of the established radioresistance mechanisms involves adaptation of cancer cells to an elevated levels of reactive oxygen species (ROS) by activating antioxidant systems (AOS) of cellular protection and survival. Since radiotherapy mainly relies on ROS production that damages DNA, causing cancer cell death, activation of the AOS can mitigate radiotherapy effectiveness. Therefore, suppressing the AOS and its associated adaptation mechanisms may increase tumour radiosensitivity and enhance treatment outcomes. In this review, we discuss the role of one of the key components of the cellular AOS which is under the control of the NRF2 transcription factor (nuclear erythroid factor 2) – a master regulator of cellular redox balance that protects cells from oxidative stress during radiotherapy by governing expression of a battery of antioxidant enzymes. We first outline the molecular mechanism of the redox-sensitive NRF2 AOS and its activation in response to the increased ROS levels following irradiation. We then evaluate experimental and clinical evidence regarding NRF2 activation in various cancer cells and tumours exposed to ionizing irradiation. Furthermore, we discuss results of numerous experimental and clinical investigations demonstrating that suppression of the NRF2 AOS enhances radiosensitivity of various cancers and improves radiotherapy outcomes. Collectively, these findings confirmed the potential of combining radiotherapy with targeted therapy aiming at the suppression of the NRF2 AOS. In this combination therapy NRF2 inhibitors act as radiosensitizers that promote overcoming radioresistance due to extra ROS accumulation and oxidative stress induction in cancer cells by inhibition of the NRF2-dependent antioxidant responses to radiotherapy.