title: Treatment of doxorubicin-resistant MCF7/Dx cells with nitric oxide causes histone glutathionylation and reversal of drug resistance.
abstract: 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.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: de Luca
authors.forename: Noemi
authors.initials: N
authors.lastname: Moroni
authors.forename: Annalucia
authors.initials: A
authors.lastname: Serafino
authors.forename: Alessandra
authors.initials: A
authors.lastname: Primavera
authors.forename: Anna
authors.initials: A
authors.lastname: Pastore
authors.forename: Jens Z
authors.initials: JZ
authors.lastname: Pedersen
authors.forename: Raffaele
authors.initials: R
authors.lastname: Petruzzelli
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Farrace
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pierimarchi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Moroni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Federici
authors.forename: Paola
authors.initials: P
authors.lastname: Sinibaldi Vallebona
authors.forename: Mario
authors.initials: M
authors.lastname: Lo Bello
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy; D056831:Coordination Complexes / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000494:pharmacology*; D026422:S-Nitrosoglutathione / Q000494:pharmacology
chemical_list: D056831:Coordination Complexes; D006657:Histones; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D004317:Doxorubicin; D051549:Glutathione S-Transferase pi; D005978:Glutathione