Reactive oxygen species (ROS) are a group of short-lived, highly reactive, oxygen-containing molecules that can induce DNA damage and affect the DNA damage response (DDR). There is unequivocal pre-clinical and clinical evidence that ROS influence the genotoxic stress caused by chemotherapeutics agents and ionizing radiation. Recent studies have provided mechanistic insight into how ROS can also influence the cellular response to DNA damage caused by genotoxic therapy, especially in the context of Double Strand Breaks (DSBs). This has led to the clinical evaluation of agents modulating ROS in combination with genotoxic therapy for cancer, with mixed success so far. These studies point to context dependent outcomes with ROS modulator combinations with Chemotherapy and radiotherapy, indicating a need for additional pre-clinical research in the field. In this review, we discuss the current knowledge on the effect of ROS in the DNA damage response, and its clinical relevance.

ROS and the DNA damage response in cancer.

Purpose: Humans are increasingly exposed to ionizing radiation (IR). Both low (<100 mGy) and high doses can cause stochastic effects, including cancer; whereas doses above 100 mGy are needed to promote tissue or cell damage. 10-15% of radiotherapy (RT) patients suffer adverse reactions, described as displaying radiosensitivity (RS). Sensitivity to IR's stochastic effects is termed radiosusceptibility (RSu). To optimize radiation protection we need to understand the range of individual variability and underlying mechanisms. We review the potential mechanisms contributing to RS/RSu focusing on RS following RT, the most tractable RS group.Conclusions: The IR-induced DNA damage response (DDR) has been well characterized. Patients with mutations in the DDR have been identified and display marked RS but they represent only a small percentage of the RT patients with adverse reactions. We review the impacting mechanisms and additional factors influencing RS/RSu. We discuss whether RS/RSu might be genetically determined. As a recommendation, we propose that a prospective study be established to assess RS following RT. The study should detail tumor site and encompass a well-defined grading system. Predictive assays should be independently validated. Detailed analysis of the inflammatory, stress and immune responses, mitochondrial function and life style factors should be included. Existing cohorts should also be optimally exploited.

Establishing mechanisms affecting the individual response to ionizing radiation

Impact of Low-dose Ionising Radiation on the Composition of the Gut Microbiota of Mice

The precise mechanism of intercellular communication between cancer cells following radiation exposure is unclear Exosomes are membrane‑enclosed small vesicles comprising lipid bilayers and are mediators of intercellular communication that transport a variety of intracellular components, including microRNAs (miRNAs or miRs) The present study aimed to identify novel roles of exosomes released from irradiated cells to neighboring cancer cells In order to confirm the presence of exosomes in the human pancreatic cancer cell line MIAPaCa‑2, ultracentrifugation was performed followed by transmission electron microscopy and nanoparticle tracking analysis (NanoSight) using the exosome‑specific surface markers CD9 and CD63 Subsequent endocytosis of exosomes was confirmed by fluorescent microscopy Cell survival following irradiation and the addition of exosomes was evaluated by colony forming assay Expression levels of miRNAs in exosomes were then quantified by microarray analysis, while protein expression levels of Cu/Zn‑ and Mn‑superoxide dismutase (SOD1 and 2, respectively) enzymes in MIAPaCa‑2 cells were evaluated by western blotting Results showed that the uptake of irradiated exosomes was significantly higher than that of non‑irradiated exosomes Notably, irradiated exosomes induced higher intracellular levels of reactive oxygen species (ROS) and a higher frequency of DNA damage in MIAPaCa‑2 cells, as determined by fluorescent microscopy and immunocytochemistry, respectively Moreover, six up‑ and five downregulated miRNAs were identified in 5 and 8 Gy‑irradiated cells using miRNA microarray analyses Further analysis using miRNA mimics and reverse transcription‑quantitative PCR identified miR‑6823‑5p as a potential candidate to inhibit SOD1, leading to increased intracellular ROS levels and DNA damage To the best of our knowledge, the present study is the first to demonstrate that irradiated exosomes enhance the radiation effect via increasing intracellular ROS levels in cancer cells This contributes to improved understanding of the bystander effect of neighboring cancer cells

/pdf/exosome-mediated-radiosensitizing-effect-on-neighboring-16q994zwks.pdf

Exosome-mediated radiosensitizing effect on neighboring cancer cells via increase in intracellular levels of reactive oxygen species.

Radiotherapy and chemotherapy are the most effective nonsurgical treatments for cancer treatment. They usually induce regulated cell death by increasing the level of reactive oxygen species (ROS) in tumour cells. However, as intracellular ROS concentration increases, many antioxidant pathways are concurrently upregulated by cancer cells to inhibit ROS production, ultimately leading to drug resistance. Understanding the mechanism of antioxidant stress in tumour cells provides a new research direction for overcoming therapeutic resistance. In this review, we address (1) how radiotherapy and chemotherapy kill tumour cells by increasing the level of ROS, (2) the mechanism by which ROS activate antioxidant pathways and the subsequent cellular mitigation of ROS in radiotherapy and chemotherapy treatments, and (3) the potential research direction for targeted treatment to overcome therapeutic resistance.

/pdf/antioxidative-stress-inhibiting-reactive-oxygen-species-20fmlg38b3.pdf

Antioxidative Stress: Inhibiting Reactive Oxygen Species Production as a Cause of Radioresistance and Chemoresistance.

Quantitative proteomics reveals mitochondrial respiratory chain as a dominant target for carbon ion radiation: Delayed reactive oxygen species generation caused DNA damage.

Peng-Cheng Fan

Papers

Quantitative proteomics reveals mitochondrial respiratory chain as a dominant target for carbon ion radiation: Delayed reactive oxygen species generation caused DNA damage.