Inhibiting catalase activity sensitizes 36B10 rat glioma cells to oxidative stress.
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| Abstract |
Gliomas are extremely resistant to anticancer therapies resulting in poor patient survival, due, in part, to altered expression of antioxidant enzymes. The primary antioxidant enzyme, catalase, is elevated constitutively in gliomas compared to normal astrocytes. We hypothesized that downregulating catalase in glioma cells would sensitize these cells to oxidative stress. To test this hypothesis, we implemented two approaches. The first, a pharmacological approach, used 3-amino-1,2,4-triazole, an irreversible inhibitor that reduced catalase enzymatic activity by 75%. Pharmacological inhibition of catalase was not associated with a reduction in rat 36B10 glioma cell viability until the cells were challenged with additional oxidative stress, i.e., ionizing radiation or hydrogen peroxide (H(2)O(2)). In the second molecular approach, we generated 36B10 glioma cells stably expressing catalase shRNA; a stable cell line displayed a 75% reduction in catalase immunoreactive protein and enzymatic activity. This was accompanied by an increase in intracellular reactive oxygen species and extracellular H(2)O(2). These cells exhibited increased sensitivity to radiation and H(2)O(2), which was rescued by the antioxidant, N-acetylcysteine. These results support the hypothesis that catalase is a major participant in the defense of 36B10 glioma cells against oxidative stress mediated by anticancer agents capable of increasing steady-state levels of H(2)O(2).
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| Authors | Pameeka S Smith, Weiling Zhao, Douglas R Spitz, Mike E Robbins |
| Journal | Free radical biology & medicine (Free Radic Biol Med) Vol. 42 Issue 6 Pg. 787-97 (Mar 15 2007) ISSN: 0891-5849 [Print] United States |
| PMID | 17320761 (Publication Type: Journal Article, Research Support, N.I.H., Extramural) |
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