{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1361137046480923776.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1016/j.lfs.2004.05.040"}},{"identifier":{"@type":"URI","@value":"https://api.elsevier.com/content/article/PII:S0024320504009877?httpAccept=text/xml"}},{"identifier":{"@type":"URI","@value":"https://api.elsevier.com/content/article/PII:S0024320504009877?httpAccept=text/plain"}},{"identifier":{"@type":"PMID","@value":"15680309"}},{"identifier":{"@type":"NAID","@value":"30004820698"}}],"dc:title":[{"@value":"Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide"}],"description":[{"notation":[{"@value":"The main anticancer action of doxorubicin (DOX) is believed to be due to topoisomerase II inhibition and free radical generation. Our previous study has demonstrated that TAS-103, a topoisomerase inhibitor, induces apoptosis through DNA cleavage and subsequent H(2)O(2) generation mediated by NAD(P)H oxidase activation [H. Mizutani et al. J. Biol. Chem. 277 (2002) 30684-30689]. Therefore, to clarify whether DOX functions as an anticancer drug through the same mechanism or not, we investigated the mechanism of apoptosis induced by DOX in the human leukemia cell line HL-60 and the H(2)O(2)-resistant sub-clone, HP100. DOX-induced DNA ladder formation could be detected in HL-60 cells after a 7 h incubation, whereas it could not be detected under the same condition in HP100 cells, suggesting the involvement of H(2)O(2)-mediated pathways in apoptosis. Flow cytometry revealed that H(2)O(2) formation preceded the increase in Delta Psi m and caspase-3 activation. Poly(ADP-ribose) polymerase (PARP) and NAD(P)H oxidase inhibitors prevented DOX-induced DNA ladder formation in HL-60 cells. Moreover, DOX significantly induced formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine, an indicator of oxidative DNA damage, in HL-60 cells at 1 h, but not in HP100 cells. DOX-induced apoptosis was mainly initiated by oxidative DNA damage in comparison with the ability of other topoisomerase inhibitors (TAS-103, amrubicin and amrubicinol) to cause DNA cleavage and apoptosis. These results suggest that the critical apoptotic trigger of DOX is considered to be oxidative DNA damage by the DOX-induced direct H(2)O(2) generation, although DOX-induced apoptosis may involve topoisomerase II inhibition. This oxidative DNA damage causes indirect H(2)O(2) generation through PARP and NAD(P)H oxidase activation, leading to the Delta Psi m increase and subsequent caspase-3 activation in DOX-induced apoptosis."}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1381137046480923777","@type":"Researcher","foaf:name":[{"@value":"Hideki Mizutani"}]},{"@id":"https://cir.nii.ac.jp/crid/1381137046480923778","@type":"Researcher","foaf:name":[{"@value":"Saeko Tada-Oikawa"}]},{"@id":"https://cir.nii.ac.jp/crid/1381137046480923779","@type":"Researcher","foaf:name":[{"@value":"Yusuke Hiraku"}]},{"@id":"https://cir.nii.ac.jp/crid/1381137046480923776","@type":"Researcher","foaf:name":[{"@value":"Michio Kojima"}]},{"@id":"https://cir.nii.ac.jp/crid/1381137046480923780","@type":"Researcher","foaf:name":[{"@value":"Shosuke Kawanishi"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"00243205"}],"prism:publicationName":[{"@value":"Life Sciences"}],"dc:publisher":[{"@value":"Elsevier BV"}],"prism:publicationDate":"2005-02","prism:volume":"76","prism:number":"13","prism:startingPage":"1439","prism:endingPage":"1453"},"reviewed":"false","dc:rights":["https://www.elsevier.com/tdm/userlicense/1.0/","https://www.elsevier.com/legal/tdmrep-license"],"url":[{"@id":"https://api.elsevier.com/content/article/PII:S0024320504009877?httpAccept=text/xml"},{"@id":"https://api.elsevier.com/content/article/PII:S0024320504009877?httpAccept=text/plain"}],"createdAt":"2005-01-25","modifiedAt":"2025-09-20","foaf:topic":[{"@id":"https://cir.nii.ac.jp/all?q=Apoptosis","dc:title":"Apoptosis"},{"@id":"https://cir.nii.ac.jp/all?q=HL-60%20Cells","dc:title":"HL-60 Cells"},{"@id":"https://cir.nii.ac.jp/all?q=Poly(ADP-ribose)%20Polymerase%20Inhibitors","dc:title":"Poly(ADP-ribose) Polymerase Inhibitors"},{"@id":"https://cir.nii.ac.jp/all?q=Membrane%20Potentials","dc:title":"Membrane Potentials"},{"@id":"https://cir.nii.ac.jp/all?q=Electrochemistry","dc:title":"Electrochemistry"},{"@id":"https://cir.nii.ac.jp/all?q=Humans","dc:title":"Humans"},{"@id":"https://cir.nii.ac.jp/all?q=Anthracyclines","dc:title":"Anthracyclines"},{"@id":"https://cir.nii.ac.jp/all?q=Enzyme%20Inhibitors","dc:title":"Enzyme Inhibitors"},{"@id":"https://cir.nii.ac.jp/all?q=Chromatography,%20High%20Pressure%20Liquid","dc:title":"Chromatography, High Pressure Liquid"},{"@id":"https://cir.nii.ac.jp/all?q=Antibiotics,%20Antineoplastic","dc:title":"Antibiotics, Antineoplastic"},{"@id":"https://cir.nii.ac.jp/all?q=Caspase%203","dc:title":"Caspase 3"},{"@id":"https://cir.nii.ac.jp/all?q=Deoxyguanosine","dc:title":"Deoxyguanosine"},{"@id":"https://cir.nii.ac.jp/all?q=NADPH%20Oxidases","dc:title":"NADPH Oxidases"},{"@id":"https://cir.nii.ac.jp/all?q=DNA","dc:title":"DNA"},{"@id":"https://cir.nii.ac.jp/all?q=Hydrogen%20Peroxide","dc:title":"Hydrogen Peroxide"},{"@id":"https://cir.nii.ac.jp/all?q=Flow%20Cytometry","dc:title":"Flow Cytometry"},{"@id":"https://cir.nii.ac.jp/all?q=Indenes","dc:title":"Indenes"},{"@id":"https://cir.nii.ac.jp/all?q=8-Hydroxy-2'-Deoxyguanosine","dc:title":"8-Hydroxy-2'-Deoxyguanosine"},{"@id":"https://cir.nii.ac.jp/all?q=Doxorubicin","dc:title":"Doxorubicin"},{"@id":"https://cir.nii.ac.jp/all?q=Caspases","dc:title":"Caspases"},{"@id":"https://cir.nii.ac.jp/all?q=Aminoquinolines","dc:title":"Aminoquinolines"},{"@id":"https://cir.nii.ac.jp/all?q=Topoisomerase%20I%20Inhibitors","dc:title":"Topoisomerase I Inhibitors"},{"@id":"https://cir.nii.ac.jp/all?q=DNA%20Damage","dc:title":"DNA Damage"}],"relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360565168214740736","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"17β‐Oestradiol inhibits doxorubicin‐induced apoptosis via block of the volume‐sensitive Cl<sup>‐</sup>current in rabbit 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