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001-es BibID:	BIBFORM047643
035-os BibID:	PMID:14599773
Első szerző:	Boldogh István
Cím:	Reduced DNA double strand breaks in chlorambucil resistant cells are related to high DNA-PKcs activity and low oxidative stress / Istvan Boldogh, Gargi Roy, Myung-Soog Lee, Attila Bacsi, Tapas K. Hazra, Kishor K. Bhakat, Gokul C. Das, Sankar Mitra
Dátum:	2003
ISSN:	0300-483X
Megjegyzések:	Modulation of DNA repair represents a strategy to overcome acquired drug resistance of cells to genotoxic chemotherapeuticagents, including nitrogen mustards (NM). These agents induce DNA inter-strand cross-links, which in turn produce doublestrand breaks (dsbs). These breaks are primarily repaired via the nonhomologous end-joining (NHEJ) pathway.ADNA-dependentprotein kinase (DNA-PK) complex plays an important role in NHEJ, and its increased level/activity is associated with acquireddrug resistance of human tumors. We show in this report that the DNA-PK complex has comparable levels and kinase activityof 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 activityof DNA-PKcs was increased up to 2 h after Cbl treatment in both cell types; however, it subsequently decreased only in sensitivecells, which is consistent with increased levels of DNA dsbs. The decreased kinase activity of DNA-PKcs was not due to a changein its amount or the levels ofKu70 andKu86, their subcellular distribution, cell cycle progression or caspase-mediated degradationof DNA-PK. In addition to DNA cross-links, Cbl treatment of cells causes a 2.2-fold increase in the level of reactive oxygenspecies (ROS) in both cell types. However, the ROS in A2780/100 cells were reduced to the basal level after 3?4 h, while sensitivecells 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 levelsof DNA dsbs and increased cell survival. Depletion in GSH from A2780/100 cells by l-buthionine sulfoximine (BSO) resulted insustained production of ROS, loweredDNA-PKcs kinase activity, enhanced levels ofDNAdsbs, 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 ofROS could be the basis for adjuvant therapies for sensitizing tumor cells to nitrogen mustards and other DNA cross-linking drugs.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban Oxidative stress DNA-PK DNA double strand breaks
Megjelenés:	Toxicology. - 193 : 1-2 (2003), p. 137-152. -
További szerzők:	Roy, Gargi Myung-Soog, Lee Bácsi Attila (1967-) (immunológus) Hazra, Tapas K. Bhakat, Kishor K. Das, Gokul C. Mitra, Sankar
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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