Antioxidant defense mechanisms of human mesothelioma and lung adenocarcinoma cells

The development of drug resistance of tumors is multifactorial and still po orly understood. Some cytotoxic drugs generate free radicals, and, therefor e, antioxidant enzymes may contribute to drug resistance. We investigated t he levels of manganese superoxide dismutase (Mn SOD), its inducibility, and its protective role against tumor necrosis factor-alpha and cytotoxic drug s (cisplatin, epirubicin, methotrexate, and vindesin) in human pleural meso thelioma (M14K) and pulmonary adenocarcinoma (A549) cells. We also studied other major antioxidant mechanisms in relation to oxidant and drug resistan ce of these cells. A549 cells were more resistant than M14K cells toward bo th oxidants (hydrogen peroxide and menadione) and all the cytotoxic drugs t ested. M14K cells contained higher basal Mn SOD activity than A549 cells (2 8.3 +/- 3.4 vs. 1.8 +/- 0.3 U/mg protein), and Mn SOD activity was signific antly induced by tumor necrosis factor-alpha only in A549 cells (+524%), bu t the induction did not offer any protection during subsequent oxidant or d rug exposure. Mn SOD was not induced significantly in either of these cell lines by any of the cytotoxic drugs (0.007-2 mu M, 48 h) tested when assess ed by Northern blotting, Western blotting, or specific activity. A549 cells contained higher catalase activity than M14K cells (7.6 +/- 1.3 vs. 3.6 +/ - 0.5 nmol O-2.min(-1).mg protein(-1)). They also contained twofold higher levels of glutathione and higher immunoreactivity of the heavy subunit of g amma-glutamylcysteine synthetase than M14K cells. Experiments with inhibito rs of gamma-glutamylcysteine synthetase and catalase supported our conclusi on that mechanisms associated with glutathione contribute to the drug resis tance of these cells.