| Overexpression of cytochrome P450 NADPH reductase sensitises MDA 231 breast carcinoma cells to 5-fluorouracil: possible mechanisms involved. | |
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MedLine Citation:
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PMID: 18191533 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Activity of cytochromes P450 is highly dependent on cytochrome P450 NADPH reductase (P450R), but this enzyme can also metabolise drugs on its own. MDA 231 breast adenocarcinoma cells transfected with human P450R (MDA R4) or an empty vector (MDA EV) were exposed to a series of commonly used chemotherapeutic drugs. Overexpression of P450R did not affect cell sensitivity to cisplatin, mitoxantrone, paclitaxel, docetaxel, vincristine or etoposide. However, MDA R4 cells showed increased sensitivity to mitomycin C (6.6-fold) and also to 5-fluorouracil (2.8-fold). In vitro toxicity assays where mitomycin C, 5-fluorouracil and vincristine were preincubated with microsomes expressing recombinant P450R showed that this effect was not a result of direct metabolism by P450R. Levels of NADPH were considerably decreased in MDA R4 as compared to MDA EV cells, while reactive oxygen species (ROS) production was increased in MDA R4 cells in basal conditions, showing no significant further increase after treatment with mitomycin C or 5-fluorouracil. P450R overexpression appears therefore to be detrimental to MDA 231 cells, depleting NADPH and increasing ROS levels; the increased oxidative stress observed in MDA R4 cells might explain the enhanced sensitivity to 5-fluorouracil. Expression of this enzyme in tumour cells might therefore modulate response to 5-fluorouracil. |
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Authors:
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Vanesa G Martinez; Kaye J Williams; Ian J Stratford; Martin Clynes; Robert O'Connor |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-12-07 |
Journal Detail:
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Title: Toxicology in vitro : an international journal published in association with BIBRA Volume: 22 ISSN: 0887-2333 ISO Abbreviation: Toxicol In Vitro Publication Date: 2008 Apr |
Date Detail:
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Created Date: 2008-03-10 Completed Date: 2008-07-10 Revised Date: 2009-04-10 |
Medline Journal Info:
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Nlm Unique ID: 8712158 Medline TA: Toxicol In Vitro Country: England |
Other Details:
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Languages: eng Pagination: 582-8 Citation Subset: IM |
Affiliation:
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National Institute for Cellular Biotechnology (NICB), Dublin City University, Glasnevin, Dublin 9, Ireland. vanesa.martinez2@mail.dcu.ie |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antibiotics, Antineoplastic
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metabolism,
pharmacology Antimetabolites, Antineoplastic / metabolism, pharmacology* Antineoplastic Agents, Phytogenic / metabolism, pharmacology Blotting, Western Breast Neoplasms / drug therapy*, genetics Cell Line, Tumor Cell Survival Female Fluorouracil / metabolism, pharmacology* Glutathione / metabolism Humans Microsomes / metabolism Mitomycin / metabolism, pharmacology NADP / metabolism NADPH-Ferrihemoprotein Reductase / biosynthesis*, genetics, physiology Reactive Oxygen Species / metabolism Transfection Vincristine / metabolism, pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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//Medical Research Council |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Antimetabolites, Antineoplastic; 0/Antineoplastic Agents, Phytogenic; 0/Reactive Oxygen Species; 50-07-7/Mitomycin; 51-21-8/Fluorouracil; 53-59-8/NADP; 57-22-7/Vincristine; 70-18-8/Glutathione; EC 1.6.2.4/NADPH-Ferrihemoprotein Reductase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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