Acquired drug resistance was found to be suppressed in the doxorubicin-resistant breast cancer cell line MCF7/Dx after pre-treatment with GSNO (nitrosoglutathione). The effect was accompanied by enhanced protein glutathionylation and accumulation of doxorubicin in the nucleus. Among the glutathionylated proteins, we identified three members of the histone family; this is, to our knowledge, the first time that histone glutathionylation has been reported. Formation of the potential NO donor dinitrosyl–diglutathionyl–iron complex, bound to GSTP1-1 (glutathione transferase P1-1), was observed in both MCF7/Dx cells and drug-sensitive MCF7 cells to a similar extent. In contrast, histone glutathionylation was found to be markedly increased in the resistant MCF7/Dx cells, which also showed a 14-fold higher amount of GSTP1-1 and increased glutathione concentration compared with MCF7 cells. These results suggest that the increased cytotoxic effect of combined doxorubicin and GSNO treatment involves the glutathionylation of histones through a mechanism that requires high glutathione levels and increased expression of GSTP1-1. Owing to the critical role of histones in the regulation of gene expression, the implication of this finding may go beyond the phenomenon of doxorubicin resistance.
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December 2011
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Research Article|
November 14 2011
Treatment of doxorubicin-resistant MCF7/Dx cells with nitric oxide causes histone glutathionylation and reversal of drug resistance
Anastasia de Luca;
Anastasia de Luca
1
*Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica 1, 00133 Rome, Italy
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Noemi Moroni;
Noemi Moroni
1
†Institute of Translational Pharmacology, National Research Council of Italy, Via Fosso del Cavaliere 100, 00133, Rome, Italy
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Annalucia Serafino;
Annalucia Serafino
†Institute of Translational Pharmacology, National Research Council of Italy, Via Fosso del Cavaliere 100, 00133, Rome, Italy
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Alessandra Primavera;
Alessandra Primavera
*Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica 1, 00133 Rome, Italy
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Anna Pastore;
Anna Pastore
‡The Children's Hospital IRCCS “Bambino Gesù”, Piazza Sant'Onofrio 4, 00165 Rome, Italy
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Jens Z. Pedersen;
Jens Z. Pedersen
*Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica 1, 00133 Rome, Italy
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Raffaele Petruzzelli;
Raffaele Petruzzelli
§Department of Biomedical Sciences, University “G. D'Annunzio” of Chieti, Via dei Vestini 31, 66013 Chieti, Italy
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Maria Grazia Farrace;
Maria Grazia Farrace
*Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica 1, 00133 Rome, Italy
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Pasquale Pierimarchi;
Pasquale Pierimarchi
†Institute of Translational Pharmacology, National Research Council of Italy, Via Fosso del Cavaliere 100, 00133, Rome, Italy
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Gabriella Moroni;
Gabriella Moroni
¶Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata”,Via Montpellier 1, 00133 Rome, Italy
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Giorgio Federici;
Giorgio Federici
‡The Children's Hospital IRCCS “Bambino Gesù”, Piazza Sant'Onofrio 4, 00165 Rome, Italy
∥Department of Internal Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
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Paola Sinibaldi Vallebona;
Paola Sinibaldi Vallebona
¶Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata”,Via Montpellier 1, 00133 Rome, Italy
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Mario Lo Bello
Mario Lo Bello
2
*Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica 1, 00133 Rome, Italy
2To whom correspondence should be addressed (email lobello@uniroma2.it).
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Publisher: Portland Press Ltd
Received:
July 22 2011
Accepted:
August 11 2011
Accepted Manuscript online:
August 11 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 440 (2): 175–183.
Article history
Received:
July 22 2011
Accepted:
August 11 2011
Accepted Manuscript online:
August 11 2011
Citation
Anastasia de Luca, Noemi Moroni, Annalucia Serafino, Alessandra Primavera, Anna Pastore, Jens Z. Pedersen, Raffaele Petruzzelli, Maria Grazia Farrace, Pasquale Pierimarchi, Gabriella Moroni, Giorgio Federici, Paola Sinibaldi Vallebona, Mario Lo Bello; Treatment of doxorubicin-resistant MCF7/Dx cells with nitric oxide causes histone glutathionylation and reversal of drug resistance. Biochem J 1 December 2011; 440 (2): 175–183. doi: https://doi.org/10.1042/BJ20111333
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