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Radiotherapy-induced adverse effects are dose limiting factors and therefore narrow the therapeutic window. A novel potential radioprotector, Caffeic Acid Phenethyl Ester (CAPE), has been suggested to widen the therapeutic window by having cytotoxic effects in tumor cells but protecting the normal tissue against radiation. CAPE has been shown to have anti-inflammatory and anti-oxidant effects in normal tissue, while anti-proliferative and pro-apoptotic effects in tumor cells. The aim of this study is therefore to investigate the radiosensitizing effect of CAPE in a panel of lung cancer cell lines in vitro. 

Human adenocarcinoma (H1299, H1975, H522, HCC827) and non-adenocarcinoma (H520, H292) NSCLC lines were incubated for 24 hours with increasing doses of CAPE. Viability was assessed using multi-well plate alamarBlue-based viability assays. Clonogenic survival assays were used to assess the radiosensitizing properties of CAPE. Cells were incubated with CAPE (IC₂₅ and IC₅₀) for 24 hours followed by irradiation with doses up to 6 Gy, and seeded to allow colony formation. Colonies were stained and counted (>50 cells) after 11 to 15 days.

Treatment with CAPE decreased cell viability in lung cancer cells in a dose-dependent manner. IC₅₀ values varied between 32 and 88 μM. Clonogenic survival assays showed significant radiosensitization by CAPE in human lung adenocarcinoma cell lines (H1299 p<0.001, H1975 p<0.0001, H522 p<0.0001 for both CAPE concentrations IC₂₅ and IC₅₀; HCC827 p<0.0001 for CAPE IC₂₅, p<0.01 for CAPE IC₅₀). Conversely, no significant differences were found in human lung non-adenocarcinoma lines (H520 p=0.1323, H292 p=0.6456 for CAPE IC₅₀) comparing CAPE treatment combined with radiation and radiation alone. 

CAPE has cytotoxic effects in human lung cancer lines, but sensitizes only human lung adenocarcinoma lines to radiation. No radiosensitizing effect was observed in human non-adenocarcinoma lines. In attempt to explain the differences between adenocarcinoma and non-adenocarcinoma lung cancer cell lines, the study of the molecular mechanisms of CAPE-mediated radiosensitization in tumor cells, such as NF-κB pathway blockage and metabolic changes, is ongoing. Furthermore, the radioprotective effects of CAPE in normal tissue are currently being investigated.