Source:http://linkedlifedata.com/resource/pubmed/id/14599773
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1-2
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| pubmed:dateCreated |
2003-11-5
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| pubmed:abstractText |
Modulation of DNA repair represents a strategy to overcome acquired drug resistance of cells to genotoxic chemotherapeutic agents, including nitrogen mustards (NM). These agents induce DNA inter-strand cross-links, which in turn produce double strand breaks (dsbs). These breaks are primarily repaired via the nonhomologous end-joining (NHEJ) pathway. A DNA-dependent protein kinase (DNA-PK) complex plays an important role in NHEJ, and its increased level/activity is associated with acquired drug resistance of human tumors. We show in this report that the DNA-PK complex has comparable levels and kinase activity of DNA-PK catalytic subunit (DNA-PKcs) in a nearly isogenic pair of drug-sensitive (A2780) and resistant (A2780/100) cells; however, treatment with chlorambucil (Cbl), a NM-type of drug, induced differential effects in these cells. The kinase activity of DNA-PKcs was increased up to 2h after Cbl treatment in both cell types; however, it subsequently decreased only in sensitive cells, which is consistent with increased levels of DNA dsbs. The decreased kinase activity of DNA-PKcs was not due to a change in its amount or the levels of Ku70 and Ku86, their subcellular distribution, cell cycle progression or caspase-mediated degradation of DNA-PK. In addition to DNA cross-links, Cbl treatment of cells causes a 2.2-fold increase in the level of reactive oxygen species (ROS) in both cell types. However, the ROS in A2780/100 cells were reduced to the basal level after 3-4h, while sensitive cells continued to produce ROS and undergo apoptosis. Pre-treatment of A2780 cells with the glutathione (GSH) precursor, N-acetyl-L-cysteine prevented Cbl-induced increase in ROS, augmented the kinase activity of DNA-PKcs, decreased the levels of DNA dsbs and increased cell survival. Depletion in GSH from A2780/100 cells by L-buthionine sulfoximine (BSO) resulted in sustained production of ROS, lowered DNA-PKcs kinase activity, enhanced levels of DNA dsbs, and increased cell killing by Cbl. We propose that oxidative stress decreases repair of DNA dsbs via lowering kinase activity of DNA-PKcs and that induction of ROS could be the basis for adjuvant therapies for sensitizing tumor cells to nitrogen mustards and other DNA cross-linking drugs.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Alkylating,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Chlorambucil,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Neoplasm,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Reactive Oxygen Species
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| pubmed:status |
MEDLINE
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| pubmed:month |
Nov
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| pubmed:issn |
0300-483X
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
15
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| pubmed:volume |
193
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
137-52
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:14599773-Antineoplastic Agents, Alkylating,
pubmed-meshheading:14599773-Apoptosis,
pubmed-meshheading:14599773-Blotting, Western,
pubmed-meshheading:14599773-Caspases,
pubmed-meshheading:14599773-Cell Cycle,
pubmed-meshheading:14599773-Cell Line, Tumor,
pubmed-meshheading:14599773-Chlorambucil,
pubmed-meshheading:14599773-Colony-Forming Units Assay,
pubmed-meshheading:14599773-Comet Assay,
pubmed-meshheading:14599773-DNA,
pubmed-meshheading:14599773-DNA, Neoplasm,
pubmed-meshheading:14599773-DNA Damage,
pubmed-meshheading:14599773-Drug Resistance, Neoplasm,
pubmed-meshheading:14599773-Enzyme Activation,
pubmed-meshheading:14599773-Female,
pubmed-meshheading:14599773-Humans,
pubmed-meshheading:14599773-Immunohistochemistry,
pubmed-meshheading:14599773-Molecular Weight,
pubmed-meshheading:14599773-Ovarian Neoplasms,
pubmed-meshheading:14599773-Oxidative Stress,
pubmed-meshheading:14599773-Protein Kinases,
pubmed-meshheading:14599773-Reactive Oxygen Species,
pubmed-meshheading:14599773-Subcellular Fractions
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| pubmed:year |
2003
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| pubmed:articleTitle |
Reduced DNA double strand breaks in chlorambucil resistant cells are related to high DNA-PKcs activity and low oxidative stress.
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| pubmed:affiliation |
Department of Microbiology and Immunology, Sealy Center for Molecular Sciences, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. sboldogh@utmb.edu
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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