Radio-Resistance of Hypoxic Tumours: The Effects of Oxygen and Radiation on Cancer Cell Metabolism, Oxidative Stress, and DNA Repair

Cancers are often riddled with areas of low oxygen concentration (i.e. hypoxic regions) and these are, in fact, more resistant to treatments such as photon radiation which primarily relies on oxygen for the production of reactive oxygen species (ROS) to induce damage on the DNA. Cancer cells adapt to hypoxia by activating complex changes in their cellular processes, for example, in the oxidant environment and DNA damage response (DDR) as well as modifying their metabolism. The present study showed that hypoxic tumour cells from various organs have strong, albeit different, reducing capabilities and can adequately alter their energy production processes for enhanced survival and resistance to irradiation (IR). Hypoxic lung cancer cells have reduced DNA damages which correlated with their enhanced clonogenic survival. In addition, their antioxidant capacity was upregulated, resulting in a reduced cytosolic H2O2 content. Moreover, nuclear H2O2 induction of DNA double strand breaks (DSBs) was oxygen dependent, highlighting the reliance of photon IR on oxygen to generate ROS for indirect DNA damage. In conclusion, our findings highlight common and/or distinctive traits in different tumours with regions of hypoxia and elucidate the resistant behaviour of these cells, and can therefore possibly provide insight into improving radiation sensitivit