Radioprotective agents to prevent cellular damage due to ionizing radiation

Abstract

Medical imaging has become a central component of patient care to ensure early and accurate diagnosis. Unfortunately, many imaging modalities use ionizing radiation to generate images. Ionizing radiation even in low doses can cause direct DNA damage and generate reactive oxygen species and free radicals, leading to DNA, protein, and lipid membrane damage. This cell damage can lead to apoptosis, necrosis, teratogenesis, or carcinogenesis. As many as 2% of cancers (and an associated 15,000 deaths annually) can be linked to computed tomography exposure alone. Radioprotective agents have been investigated using various models including cells, animals, and recently humans. The data suggest that radioprotective agents working through a variety of mechanisms have the potential to decrease free radical damage produced by ionizing radiation. Radioprotective agents may be useful as an adjunct to medical imaging to reduced patient morbidity and mortality due to ionizing radiation exposure. Some radioprotective agents can be found in high quantities in antioxidant rich foods, suggesting that a specific diet recommendation could be beneficial in radioprotection.

Keywords: Antioxidant; Computed tomography; Ionizing radiation; Medical imaging; Mitigators; Radioprotectant.

Fig. 1

Generation of reactive oxygen species (ROS) in response to ionizing radiation. Ionizing radiation induces damage of cellular structures in two primary ways: direct damage to DNA and generation of free radical-containing reactive molecules. Free radicals are generated through the interactions between ionizing radiation and small oxygen containing molecules (including water). These interactions commonly form hydroxide and generate free electrons. Free electrons can then interact with intracellular oxygen to form superoxide. Free radicals that are generated by ionizing radiation can react with DNA, lipid membranes, and proteins causing damage and/or dysfunction to various cellular structures. The cell has mechanisms designed to mitigate and manage damage from free radicals. Hydroxide ions are reduced by the enzyme glutathione peroxidase and superoxide ions are reduced to hydrogen peroxide by superoxide dismutase. Hydrogen peroxide generated by superoxide dismutase is used by catalase to generate water. Significant damage to cellular structures occurs when ionizing radiation-induced generation of radicals out-paces the cell’s ability to clear these reactive molecules

Fig. 2

Downstream molecules and effects following DNA damage due to ionizing radiation. Ionizing radiation causes damage to DNA both directly and indirectly. Indirect damage occurs through the radiation-associated formation of free radicals. Double-stranded breaks (DSBs) are the most common form of DNA damage associated with ionizing radiation. After DSBs are generated, a cascade of enzymatic processes is triggered to allow for DNA repair or to induce apoptosis. This process includes the activation of p53 and the induction of cell cycle arrest. If the damage exceeds the cell’s ability to repair itself, either apoptosis or necrosis will occur. Alternatively, there are two common mechanisms of DSB repair: Non-homologous end joining and homologous recombination. In homologous recombination, the enzymes BRCA 1 and BRCA 2 are activated and initiate repair. If repair is successful, the cell cycle can resume. If homologous recombination is unsuccessful the cell will likely undergo apoptosis. Importantly, failure of these processes in the setting of significant mutations in cell cycle regulation or the apoptotic pathway can lead to carcinogenic transformation. In non-homologous end joining, as the name suggests, non-homologous ends are joined together to mitigate DNA damage. This can lead to significant mutations in cell cycle regulation and result in carcinogenic transformation

Fig. 3

Proposed effects of radioprotectant agents in the cell cycle. This figure presents an overview of the cell cycle and includes the proposed effects of the radioprotectant agents discussed in this review. Resveratrol was one of the most widely studied in this area, having effects on cyclin expression and thus cell cycle progression. It also was shown to induce p53 [–32, 37]. Additionally, amifostine was shown in one study to induce expression of p53 and inhibit its degradation. Melatonin was shown to inhibit progression to the G0 phase in endothelial cells. Carvacrol had an inhibitory effect on cellular apoptosis. Vitamin E, kukoamine, and acteoside inhibited pro-apoptotic proteins Bax and Bak. Acteoside shown to inhibit expression of caspase 3, and thus decrease apoptosis. Similarly, atorvastatin was shown to decrease expression of caspase 3. Isofraxidin both inhibited cytochrome C and caspases, specifically caspase 3, leading to a reduction in apoptosis. Most authors proposed that the studied radioprotectants may act as free radical scavengers or inducers of natural antioxidants (see Table 1)