4778

Introduction. ROS (reactive oxygen species) may be increased in lung cancers, and antioxidant defenses altered, suggesting a role in maintenance of the transformed phenotype. Such changes have also been noted in cell lines derived from lung cancers. However, the types of ROS, related DNA damage, and antioxidant components have never been systematically investigated, to discover the generality of importance of ROS and to identify potential targets for treatments. Materials and Methods. Human lung adenocarcinoma cell lines and non-transformed HPL cells were assayed for ROS (superoxide and peroxides), DNA damage (8-oxo-dG and comet assay), antioxidant defenses (catalase, glutathione peroxidase, MnSOD, Cu/ZnSOD, peroxiredoxins 1-6) and DNA protective or repairing enzymes (OGG1, MTH1) levels. Correlations were sought among these parameters, as well as relationship with properties of the cell line, and with characteristics of the patients presenting the original tumors. Results. For DNA single-strand breaks, superoxide and OGG1 levels seemed to be the most important determining factors for DNA damage. On the other hand, levels of peroxides in the adenocarcinoma cells correlated positively with 8-oxo-dG, especially in cells with low MTH1 levels. The most important regulators of peroxides appeared to be a subset of peroxiredoxins (Prx), with significant negative correlations between peroxide levels and Prx 1, 3, 4 and 6, but not with Prx 2 and 5. Prx 4 was strongly upregulated in all the cancer lines, compared with HPL. Prx 1, 3, 4 and 6, but not Prx 2 and 5, correlated negatively with 8-oxo-dG. Peroxides correlated negatively, and Prx 1 correlated positively, with stages of the cancer from which the cell lines derived. Prxs are thiol-specific peroxidases described only recently in animals; their function is still under discussion because of much lower efficiency compared with catalase or glutathione peroxidases. Conclusions. A subset of Prx isoforms clearly plays a dominant role in establishment of steady-state levels of peroxides in lung adenocarcinoma cell lines. Results are consistent with a current view that Prxs regulate signaling functions of peroxides; reduction in the latter correlated with higher cancer stage. OGG1 seems to play a role in containing ROS-related DNA damage. Understanding of how these components of complex redox balance pathways may contribute to maintenance of the malignant state may aid in development of therapeutic approaches.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]