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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
2003-12-5
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pubmed:abstractText |
Adaphostin (NSC 680410), an analog of the tyrphostin AG957, was previously shown to induce Bcr/abl down-regulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/abl- cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wild-type p53, a typical DNA damage response consisting of p53 phosphorylation and up-regulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Acetylcysteine,
http://linkedlifedata.com/resource/pubmed/chemical/Adamantane,
http://linkedlifedata.com/resource/pubmed/chemical/Antioxidants,
http://linkedlifedata.com/resource/pubmed/chemical/Buthionine Sulfoximine,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Neoplasm,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Fusion Proteins, bcr-abl,
http://linkedlifedata.com/resource/pubmed/chemical/Glutathione,
http://linkedlifedata.com/resource/pubmed/chemical/Hydroquinones,
http://linkedlifedata.com/resource/pubmed/chemical/NSC 680410,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Quinones,
http://linkedlifedata.com/resource/pubmed/chemical/Reactive Oxygen Species,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrphostins,
http://linkedlifedata.com/resource/pubmed/chemical/tyrphostin AG957
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0006-4971
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pubmed:author |
pubmed-author:AdjeiAlex AAA,
pubmed-author:BoneNancyN,
pubmed-author:BruzekLaura MLM,
pubmed-author:ChandraJoyaJ,
pubmed-author:HackbarthJenniferJ,
pubmed-author:KarpJudith EJE,
pubmed-author:KaufmannScott HSH,
pubmed-author:KayNeil ENE,
pubmed-author:LoegeringDavidD,
pubmed-author:NarayananVen LVL,
pubmed-author:SausvilleEdward AEA,
pubmed-author:TefferiAyalewA,
pubmed-author:UmaBB
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
102
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4512-9
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:12920036-Acetylcysteine,
pubmed-meshheading:12920036-Adamantane,
pubmed-meshheading:12920036-Antioxidants,
pubmed-meshheading:12920036-Apoptosis,
pubmed-meshheading:12920036-Buthionine Sulfoximine,
pubmed-meshheading:12920036-DNA, Neoplasm,
pubmed-meshheading:12920036-DNA Damage,
pubmed-meshheading:12920036-Enzyme Inhibitors,
pubmed-meshheading:12920036-Fusion Proteins, bcr-abl,
pubmed-meshheading:12920036-Glutathione,
pubmed-meshheading:12920036-Humans,
pubmed-meshheading:12920036-Hydroquinones,
pubmed-meshheading:12920036-K562 Cells,
pubmed-meshheading:12920036-Leukemia,
pubmed-meshheading:12920036-Leukemia, Lymphocytic, Chronic, B-Cell,
pubmed-meshheading:12920036-Leukemia, Myelogenous, Chronic, BCR-ABL Positive,
pubmed-meshheading:12920036-Leukemia, Myeloid,
pubmed-meshheading:12920036-Neoplasm Proteins,
pubmed-meshheading:12920036-Neoplastic Stem Cells,
pubmed-meshheading:12920036-Quinones,
pubmed-meshheading:12920036-Reactive Oxygen Species,
pubmed-meshheading:12920036-Tumor Stem Cell Assay,
pubmed-meshheading:12920036-Tyrphostins
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pubmed:year |
2003
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pubmed:articleTitle |
Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells.
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pubmed:affiliation |
Division of Oncology Research, Guggenheim 1301, Mayo Clinic, 200 First St, SW, Rochester, MN 55901, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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