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2013-05-13

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cc-by (c) Barros, Susana et al., 2013
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/49868

The redox state of cytochrome C modulates resistance to methotrexate in human MCF7 breast cancer cells

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http://dx.doi.org/10.1371/journal.pone.0063276

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.

Subject

Metotrexat, Càncer de mama, Quimioteràpia del càncer, Cèl·lules canceroses, Resistència als medicaments, Apoptosi

Subject (English)

Methotrexate, Breast cancer, Cancer chemotherapy, Cancer cells, Drug resistance, Apoptosis

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Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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BARROS, Susana Raquel Costa, et al. The redox state of cytochrome C modulates resistance to methotrexate in human MCF7 breast cancer cells. PLoS One. 2013. Vol. 8, num. 5, pags. e63276. ISSN 1932-6203. [consulted: 16 of August of 2026]. Available at: https://hdl.handle.net/2445/49868

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