Association between radiation-induced cell death and clinically relevant radioresistance

Radiotherapy (RT) is one of the major modalities for the treatment of human cancer and has been established as an excellent local treatment for malignant tumors. However, the existence of radioresistant cells remains one of the most critical obstacles in RT. To know the characteristics of radioresistant cells, clinically relevant radioresistant (CRR) cell lines were established. CRR cells can continue to proliferate in vitro and in vivo after exposure to 2 Gy/day of X-rays for more than 30 days. Daily microscopic observation of the irradiated CRR cells has indicated that the increase in cell death is not observed within 7 days of irradiation with 10 Gy of X-rays, suggesting that cell death is involved in cellular radioresistance. Radiation-induced regulated cell death (RCD) can be classified into three categories: apoptosis, autophagy-dependent cell death and necrosis (necroptosis). This review focuses on an aspect of radiation-induced RCD that has often been neglected: the manner in which the cells are destroyed. In many studies, apoptosis is considered the primary mode of RCD in irradiated cancer cells; however, it is necessary to consider necrosis or necroptosis as one of the modes of radiation-induced RCD.