Host: The Japan Radiation Research Society
While it has been well-known that ionizing radiation (IR) causes the formation of reactive oxygen species (ROS) through ionization and excitation of water, IR has been shown to stimulate intracellular ROS production several hours after irradiation. Recently, it is becoming clear that this secondarily-generated ROS after IR has a variety of biological roles, including apoptosis signaling, radiation-induced genetic instability, and bystander effect. However, the mechanism of IR-induced mitochondrial ROS production has not been fully elucidated. We have been investigated it by using tumor cell lines such as human lung carcinoma A549 cells. Our study revealed that IR increased mitochondrial ROS level, accompanied by the enhancement of mitochondria electron transport chain (ETC) activity. It was suggested that the increase of mitochondrial content in cells rather than the increase of ETC enzyme complex activities was involved in this IR-induced ETC activity. Irradiated cells undergo cell cycle arrest by checkpoint mechanisms. We examined the relationship between cell cycle and mitochondrial ROS level or mitochondrial content, and found that the cells at G2/M phase had higher mitochondrial ROS level and mitochondrial content than the cells at G1 or S phase. Therefore, it was suggested that IR-induced G2 arrest contributed to the increase of mitochondrial ROS level by accumulating cells at G2/M phase.
Recent evidences indicate that tumor cells have lower antioxidant capacity and are more susceptible to oxidative stress than normal cells. We thus hypothesized that drugs that increase IR-induced mitochondrial ROS production could enhance radiosensitivity of tumor cells. We have been testing several candidate compounds to verify this hypothesis. We would like to introduce our up-to-date data on it in this talk.
