Hypoxia-Induced Radioresistance in Human Non-Small Cell Lung Carcinoma Cell Lines

Abstract

Lung cancer accounts for 25 % of cancer-related deaths. Non-small cell lung carcinoma (NSCLC) constitutes 85 % of all lung cancers. Radiotherapy is used in treatment of over half of lung cancer patients. Tumor hypoxia is associated with treatment resistance particularly in the context of radiotherapy. Targeting tumor hypoxia to increase radiotherapy efficacy has met limited success clinically with no measurable mortality benefit. High linear energy transfer (LET) carbon ions are being used increasingly in cancer clinical trials and have the theoretical advantage of being less sensitive to the influence of oxygen. Studying DNA damage response (DDR) to low- (X-rays) and high-LET ionizing radiation under hypoxia may help identify molecular processes that can be potentially targeted therapeutically to overcome hypoxiainduced radioresistance. Additionally, tumor cells often experience reversible hypoxia due to tumor shrinkage secondary to treatment, neo-angiogenesis as well as intermittent vasospasm of feeding vessels. Thus, impact of reoxygenation on radioresistance also warrants greater understanding. The Nuclear Factor kB (NF-kB) pathway is associated with cellular inflammatory response to stressors like ionizing radiation and hypoxia and has been associated with enhanced cell survival. However, the role of NF-kB pathway in hypoxiainduced radioresistance remains elusive. Therefore, the radioresistance of NSCLC cells was evaluated under continuous hypoxia and following reoxygenation by performing clonogenic assays following irradiation with the objective of correlating hypoxia induced radioresistance in NSCLC cells to DDR in terms of DNA double strand break (DSB) induction, DSB repair, cell cycle progression as well as activation of pro-survival NF-kB pathway.[...]