Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/41109
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dc.contributor.authorMoreira, Ana C.-
dc.contributor.authorBranco, Ana F.-
dc.contributor.authorSampaio, Susana F.-
dc.contributor.authorCunha-Oliveira, Teresa-
dc.contributor.authorMartins, Tatiana R.-
dc.contributor.authorHoly, Jon-
dc.contributor.authorOliveira, Paulo J.-
dc.contributor.authorSardão, Vilma A.-
dc.date.accessioned2017-05-03T20:06:53Z-
dc.date.available2017-05-03T20:06:53Z-
dc.date.issued2014-12-
dc.identifier.urihttps://hdl.handle.net/10316/41109-
dc.description.abstractThe cardiotoxicity induced by the anti-cancer doxorubicin involves increased oxidative stress, disruption of calcium homeostasis and activation of cardiomyocyte death. Nevertheless, antioxidants and caspase inhibitors often show little efficacy in preventing cell death. We hypothesize that a caspase-independent cell death mechanism with the release of the apoptosis-inducing factor from mitochondria is involved in doxorubicin toxicity. To test the hypothesis, H9c2 cardiomyoblasts were used as model for cardiac cells. Our results demonstrate that z-VAD-fmk, a pan-caspase inhibitor, does not prevent doxorubicin toxicity in this cell line. Doxorubicin treatment results in AIF translocation to the nuclei, as confirmed by Western Blotting of cell fractions and confocal microscopy. Also, doxorubicin treatment of H9c2 cardiomyoblasts resulted in the appearance of 50kbp DNA fragments, a hallmark of apoptosis-inducing factor nuclear effects. Apoptosis-inducing factor knockdown using a small-interfering RNA approach in H9c2 cells resulted in a reduction of doxorubicin toxicity, including decreased p53 activation and poly-ADP-ribose-polymerase cleavage. Among the proteases that could be responsible for apoptosis-inducing factor cleavage, doxorubicin decreased calpain activity but increased cathepsin B activation, with inhibition of the latter partly decreasing doxorubicin toxicity. Altogether, the results support that apoptosis-inducing factor release is involved in doxorubicin-induced H9c2 cell death, which explains the limited ability of caspase inhibitors to prevent toxicity.por
dc.language.isoporpor
dc.rightsopenAccesspor
dc.subjectActive Transport, Cell Nucleuspor
dc.subjectAmino Acid Chloromethyl Ketonespor
dc.subjectAnimalspor
dc.subjectAntibiotics, Antineoplasticpor
dc.subjectApoptosispor
dc.subjectApoptosis Inducing Factorpor
dc.subjectBlotting, Westernpor
dc.subjectCaspase Inhibitorspor
dc.subjectCaspasespor
dc.subjectCell Linepor
dc.subjectCell Nucleuspor
dc.subjectCell Survivalpor
dc.subjectDNA Fragmentationpor
dc.subjectDose-Response Relationship, Drugpor
dc.subjectDoxorubicinpor
dc.subjectMicroscopy, Confocalpor
dc.subjectMitochondriapor
dc.subjectModels, Biologicalpor
dc.subjectMyocytes, Cardiacpor
dc.subjectRNA Interferencepor
dc.subjectRatspor
dc.subjectTime Factorspor
dc.titleMitochondrial apoptosis-inducing factor is involved in doxorubicin-induced toxicity on H9c2 cardiomyoblastspor
dc.typearticle-
degois.publication.firstPage2468-78por
degois.publication.lastPage2478por
degois.publication.issue12 Pt Apor
degois.publication.titleBiochimica et biophysica actapor
dc.peerreviewedyespor
dc.identifier.doi10.1016/j.bbadis.2014.09.015-
dc.identifier.doi10.1016/j.bbadis.2014.09.015por
degois.publication.volume1842por
item.openairetypearticle-
item.languageiso639-1pt-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.grantfulltextopen-
item.fulltextCom Texto completo-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.orcid0000-0002-7382-0339-
crisitem.author.orcid0000-0002-5201-9948-
crisitem.author.orcid0000-0001-7014-4614-
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
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