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Title: The redox state of cytochrome C modulates resistance to methotrexate in human MCF7 breast cancer cells
Author: Barros, Susana
Mencia, Núria
Rodríguez Gallego, Laura
Oleaga Sancho, Carlota
Santos, Conceição
Noé Mata, Verónica
Ciudad i Gómez, Carlos Julián
Keywords: Metotrexat
Càncer de mama
Quimioteràpia del càncer
Cèl·lules canceroses
Resistència als medicaments
Breast cancer
Cancer chemotherapy
Cancer cells
Drug resistance
Issue Date: 13-May-2013
Publisher: Public Library of Science (PLoS)
Abstract: Background: Methotrexate is a chemotherapeutic agent used to treat a variety of cancers. However, the occurrence of resistance limits its effectiveness. Cytochrome c in its reduced state is less capable of triggering the apoptotic cascade. Thus, we set up to study the relationship among redox state of cytochrome c, apoptosis and the development of resistance to methotrexate in MCF7 human breast cancer cells. Results: Cell incubation with cytochrome c-reducing agents, such as tetramethylphenylenediamine, ascorbate or reduced glutathione, decreased the mortality and apoptosis triggered by methotrexate. Conversely, depletion of glutathione increased the apoptotic action of methotrexate, showing an involvement of cytochrome c redox state in methotrexateinduced apoptosis. Methotrexate-resistant MCF7 cells showed increased levels of endogenous reduced glutathione and a higher capability to reduce exogenous cytochrome c. Using functional genomics we detected the overexpression of GSTM1 and GSTM4 in methotrexate-resistant MCF7 breast cancer cells, and determined that methotrexate was susceptible of glutathionylation by GSTs. The inhibition of these GSTM isoforms caused an increase in methotrexate cytotoxicity in sensitive and resistant cells. Conclusions: We conclude that overexpression of specific GSTMs, GSTM1 and GSTM4, together with increased endogenous reduced glutathione levels help to maintain a more reduced state of cytochrome c which, in turn, would decrease apoptosis, thus contributing to methotrexate resistance in human MCF7 breast cancer cells.
Note: Reproducció del document publicat a:
It is part of: PLoS One, 2013, vol. 8, num. 5, p. e63276
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ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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