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Cellular resistance to oxidative stress is accompanied by resistance to cisplatin: The significance of increased catalase activity and total glutathione in hydrogen peroxide‐resistant fibroblasts
Author(s) -
Spitz Douglas R.,
Phillips John W.,
Adams Donna T.,
Sherman C. Michael,
Deen Dennis F.,
Li Gloria C.
Publication year - 1993
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.1041560111
Subject(s) - cisplatin , buthionine sulfoximine , catalase , glutathione , oxidative stress , cytotoxicity , dna damage , chemistry , clonogenic assay , cell culture , hydrogen peroxide , biochemistry , pharmacology , biology , microbiology and biotechnology , cell , enzyme , dna , in vitro , chemotherapy , genetics
Abstract Studies designed to better understand the involvement of cellular resistance to oxidative stress in mechanisms of cellular resistance to cisplatin were undertaken using H 2 O 2 ‐resistant variants of the HA 1 Chinese hamster fibroblast cell line. H 2 O 2 ‐resistant cell lines were resistant to clonogenic inactivation mediated by cisplatin with dose modifying factors at 10% survival of 1.5–3.0, relative to HA 1 cells. The most cisplatin resistant of these cell lines (OC5) also demonstrated fewer DNA–DNA crosslinks induced by cisplatin, relative to HA 1. Since H 2 O 2 ‐resistant cells contained increased catalase activity as well as total glutathione (GSH) content, the involvement of these cellular antioxidants in the resistance to cisplatin toxicity was evaluated. Treatment of HA 1 and H 2 O 2 ‐resistant cell lines (OC5, OC14) with 9 mM aminotriazole reduced catalase activity by 60–65% but had no effect on the cytotoxicity of cisplatin. In contrast, treatment with 5 mM buthionine sulfoximine reduced total GSH by 90% and sensitized the cells to cisplatin cytotoxicity. Furthermore, extracellular reaction of GSH with cisplatin prior to treating HA 1 cells reduced the toxicity of the compound, indicating that this reaction is capable of participating in the detoxification of cisplatin. These results indicate that cellular adaptation to oxidative stress renders cells resistant to DNA damage as well as to cytotoxicity associated with cisplatin treatment. Furthermore, increases in total GSH content (but not catalase activity) appear to partially account for cisplatin resistance demonstrated by H 2 O 2 ‐resistant cells. © 1993 Wiley‐Liss, Inc.