High Resistance to Cisplatin in Human Ovarian Cancer Cell Lines is Associated with Marked Increase of Glutathione Synthesis

Exposure of human ovarian tumor cell lines to cisplatin led to development of cell lines that exhibited increasing degrees of drug resistance, which were closely correlated with increase of the levels of cellular glutathione. Cell lines were obtained that showed 30- to 1000-fold increases in resista...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1992-04, Vol.89 (7), p.3070-3074
Main Authors: Godwin, Andrew K., Meister, Alton, O'Dwyer, Peter J., Huang, Chin Shiou, Hamilton, Thomas C., Anderson, Mary E.
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biochemistry
Biological and medical sciences
Cancer
Cell lines
Cisplatin
Complementary DNA
Drug Resistance
Enzymes
Female
Gene Expression
General aspects
Glutamate-Cysteine Ligase - metabolism
glutathione
Glutathione - metabolism
Glutathione Transferase - metabolism
Humans
In Vitro Techniques
Kidneys
Medical research
Medical sciences
Messenger RNA
Multidisciplinary Sciences
Ovarian cancer
Ovarian Neoplasms - physiopathology
ovaries
Pharmacology. Drug treatments
Reproductive system
RNA
RNA, Messenger - genetics
Science & Technology
Science & Technology - Other Topics
Tumor cell line
Tumor Cells, Cultured
Tumors
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Summary:Exposure of human ovarian tumor cell lines to cisplatin led to development of cell lines that exhibited increasing degrees of drug resistance, which were closely correlated with increase of the levels of cellular glutathione. Cell lines were obtained that showed 30- to 1000-fold increases in resistance; these cells also had strikingly increased (13- to 50-fold) levels of glutathione as compared with the drug-sensitive cells of origin. These levels of resistance to cisplatin and the cellular glutathione levels are substantially greater than previously reported. Very high cisplatin resistance was associated with enhanced expression of mRNAs for γ-glutamylcysteine synthetase and γ-glutamyl transpeptidase; immunoblots showed increase of γ-glutamylcysteine synthetase but not of glutathione synthetase. Glutathione S-transferase activity was unaffected, as determined with chlorodinitrobenzene as a substrate. These studies suggest the potential value of examining regulation of glutathione synthesis as an indicator of clinical prognosis. The highly resistant cell lines are proving useful for studying the multiple mechanisms by which tumor cells acquire drug- and radiation-resistance.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.89.7.3070