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Superoxide anions are involved in doxorubicin-induced ERK activation in hepatocyte cultures.
Ann N Y Acad Sci. 2006 Dec; 1090:419-28.AN

Abstract

Doxorubicin (DOX), an antineoplastic agent widely used for the treatment of cancer, belongs to the anthracycline family of antitumor antibiotics. DOX may undergo one-electron reduction to the corresponding semiquinone free radical by flavin-containing reductases. Under aerobic conditions, the semiquinone radical reacts rapidly with oxygen to generate superoxide anion, undergoing redox cycling. At moderate concentrations, reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. We have shown that DOX increased phosphorylation of enzymes comprising mitogen-activated protein (MAP) kinase cascades in primary hepatocyte cultures, and that this action was independent of oxidant damage. In particular, extracellular signal-regulated kinase (ERK) was phosphorylated by the drug treatment. In this work, we have determined the possible involvement of particular free radicals in DOX-induced ERK phosphorylation in hepatocyte cultures by using specific free radical scavengers. The levels of ERK phosphorylation were measured by Western blot analysis with an anti-Thr202/Tyr204-phosphorylated p44/p42 MAPK antibody. Deferoxamine (DFO; iron chelator), catalase (hydrogen peroxide-removing enzyme), or alpha-tocopherol (peroxyl-radical scavenger) did not affect DOX-increased ERK phosphorylation levels. However, the cell-permeable superoxide dismutase mimetic MnTBAP and the flavin-containing enzyme inhibitor diphenyleneiodonium reverted DOX-induced effects. These results suggest that superoxide anions, probably generated by DOX metabolism, are involved in the effects of the anthracycline on the MAP kinase cascade activation.

Authors+Show Affiliations

Department of Physiology, Medicine and Dentistry School, University of the Basque Country, 48080-Bilbao, Spain.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17384286

Citation

Navarro, Rosaura, et al. "Superoxide Anions Are Involved in Doxorubicin-induced ERK Activation in Hepatocyte Cultures." Annals of the New York Academy of Sciences, vol. 1090, 2006, pp. 419-28.
Navarro R, Busnadiego I, Ruiz-Larrea MB, et al. Superoxide anions are involved in doxorubicin-induced ERK activation in hepatocyte cultures. Ann N Y Acad Sci. 2006;1090:419-28.
Navarro, R., Busnadiego, I., Ruiz-Larrea, M. B., & Ruiz-Sanz, J. I. (2006). Superoxide anions are involved in doxorubicin-induced ERK activation in hepatocyte cultures. Annals of the New York Academy of Sciences, 1090, 419-28.
Navarro R, et al. Superoxide Anions Are Involved in Doxorubicin-induced ERK Activation in Hepatocyte Cultures. Ann N Y Acad Sci. 2006;1090:419-28. PubMed PMID: 17384286.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Superoxide anions are involved in doxorubicin-induced ERK activation in hepatocyte cultures. AU - Navarro,Rosaura, AU - Busnadiego,Idoia, AU - Ruiz-Larrea,M Begoña, AU - Ruiz-Sanz,José Ignacio, PY - 2007/3/27/pubmed PY - 2007/4/27/medline PY - 2007/3/27/entrez SP - 419 EP - 28 JF - Annals of the New York Academy of Sciences JO - Ann N Y Acad Sci VL - 1090 N2 - Doxorubicin (DOX), an antineoplastic agent widely used for the treatment of cancer, belongs to the anthracycline family of antitumor antibiotics. DOX may undergo one-electron reduction to the corresponding semiquinone free radical by flavin-containing reductases. Under aerobic conditions, the semiquinone radical reacts rapidly with oxygen to generate superoxide anion, undergoing redox cycling. At moderate concentrations, reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. We have shown that DOX increased phosphorylation of enzymes comprising mitogen-activated protein (MAP) kinase cascades in primary hepatocyte cultures, and that this action was independent of oxidant damage. In particular, extracellular signal-regulated kinase (ERK) was phosphorylated by the drug treatment. In this work, we have determined the possible involvement of particular free radicals in DOX-induced ERK phosphorylation in hepatocyte cultures by using specific free radical scavengers. The levels of ERK phosphorylation were measured by Western blot analysis with an anti-Thr202/Tyr204-phosphorylated p44/p42 MAPK antibody. Deferoxamine (DFO; iron chelator), catalase (hydrogen peroxide-removing enzyme), or alpha-tocopherol (peroxyl-radical scavenger) did not affect DOX-increased ERK phosphorylation levels. However, the cell-permeable superoxide dismutase mimetic MnTBAP and the flavin-containing enzyme inhibitor diphenyleneiodonium reverted DOX-induced effects. These results suggest that superoxide anions, probably generated by DOX metabolism, are involved in the effects of the anthracycline on the MAP kinase cascade activation. SN - 0077-8923 UR - https://www.unboundmedicine.com/medline/citation/17384286/Superoxide_anions_are_involved_in_doxorubicin_induced_ERK_activation_in_hepatocyte_cultures_ L2 - https://doi.org/10.1196/annals.1378.045 DB - PRIME DP - Unbound Medicine ER -