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1 Childrens Hospital, University of Helsinki, 00029 Helsinki; 2 Finnish Institute of Occupational Health, 00250 Helsinki; 4 Department of Internal Medicine, University of Oulu, 90220 Oulu Finland; and 3 Department of Environmental Health, University of Washington, Seattle, Washington 98105-6099
The development of drug resistance of
tumors is multifactorial and still poorly understood. Some cytotoxic
drugs generate free radicals, and, therefore, antioxidant enzymes may
contribute to drug resistance. We investigated the levels of manganese
superoxide dismutase (Mn SOD), its inducibility, and its protective
role against tumor necrosis factor-
and cytotoxic drugs (cisplatin, epirubicin, methotrexate, and vindesin) in human pleural mesothelioma (M14K) and pulmonary adenocarcinoma (A549) cells. We also studied other
major antioxidant mechanisms in relation to oxidant and drug resistance
of these cells. A549 cells were more resistant than M14K cells toward
both oxidants (hydrogen peroxide and menadione) and all the cytotoxic
drugs tested. M14K cells contained higher basal Mn SOD activity than
A549 cells (28.3 ± 3.4 vs. 1.8 ± 0.3 U/mg protein), and Mn SOD
activity was significantly induced by tumor necrosis factor- only in
A549 cells (+524%), but the induction did not offer any protection
during subsequent oxidant or drug exposure. Mn SOD was not induced
significantly in either of these cell lines by any of the cytotoxic
drugs (0.007-2 µM, 48 h) tested when assessed 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
O2 · min
1 · mg
protein1). They also contained twofold higher levels
of glutathione and higher immunoreactivity of the heavy subunit of
-glutamylcysteine synthetase than M14K cells. Experiments with
inhibitors of -glutamylcysteine synthetase and catalase supported
our conclusion that mechanisms associated with glutathione contribute
to the drug resistance of these cells.
oxidant; hydrogen peroxide; drug; A549 cells; superoxide dismutase; catalase; glutathione; -glutamylcysteine synthetase
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