Reduced DNA double strand breaks in chlorambucil resistant cells are related to high DNA-PKcs activity and low oxidative stress

Boldogh, István; Roy, Gargi; Lee, Myung Soog; Bácsi, Attila; Hazra, Tapas K.; Bhakat, Kishor K.; Das, Gautam; Mitra, Sankar

doi:10.1016/j.tox.2003.08.013

Cited by 59 publications

(61 citation statements)

References 63 publications

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“…Earlier it was shown that DNA-PKcs do not change significantly after Cbl treatment until 3 h of treatment, but reduction of kinase activity was observed in Cbl cos -treated drug-sensitive cells. 15 It is possible that after COS treatment in Cbl-treated drug-resistant cells, DNA-PKcs catalytic subunit is degraded by caspases, 29 as previously shown in other tumor cells.…”

Section: Discussionmentioning

confidence: 90%

“…14 Therefore, the inability of cells to maintain oxidative stress may be the reason for the observed resistance in A2780/100 cells. 15 When A2780/100 cells are treated with L-buthionine (SR)-sulfoximine (BSO), a g-glutamylcysteine synthetase (a rate-limiting enzyme in glutathione (GSH) synthesis) inhibitor, 16 the percentage of cell survival significantly decreased. LD 50 of Cbl A2780/100 cells also decreases when cells are exposed to GSH-depleting agent, diethyl maleate.…”

Section: Resultsmentioning

confidence: 99%

“…Addition of NO has no effect (bar 7) on cell growth, although NOO À (1 nM) decreases (bar 8) LD 50 (Figure 1b) and signals cell death by apoptosis, as earlier evidenced in Cbl-treated A2780-sensitive cells. 2,15 Expression profiling of Cbl-sensitive A2780 and -resistant A2780/100 cells shows the expression difference for a set of genes, and those changes in gene expression due to Cbl-induced resistance in A2780/100 cells are not apparent. Validation of microarray gene expression by real-time PCR Among differentially regulated genes, five genes (CDK6, CLARP2, TSPYL4, RYBP and CYR61) are selected and their mRNA expressions are validated by real-time PCR (TaqMan method).…”

Section: Resultsmentioning

confidence: 99%

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Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Maiti

2009

Pharmacogenomics J

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Drug resistance in cancer cells involves complex molecular mechanisms and ovarian carcinoma cells become resistant to chlorambucil (Cbl) after continuous treatment. This drug-and ionizing radiation-resistant cells have lower level of endogenous ROS (reactive oxygen species) compared with sensitive cells. Elevation of the cellular ROS level by exogenous ROS generation increases the sensitivity of Cbl to resistant cells. In contrast, antioxidants prevent the sensitization of resistant cells to Cbl by H 2 O 2 , COS (chronic oxidative stress) or NOO À . The molecular mechanism of drug sensitivity with COS has been investigated by microarray gene expressions followed by gene network analysis and it reveals that a cdc42/rac1 guanine exchange factor, ARHGEF6, with p53 and DNA-Pkc (PRKDC) is central to induce apoptosis in Cbl cos (Cbl with COS) cells. mRNA and protein levels of major gene network pathway differ significantly in Cbl cos cells than in Cbltreated cells. Moreover, DNA-PKc physically interacts with ARHGEF6 and p53 mostly in the nucleus of Cbl-treated cells, whereas in Cbl cos -treated cells, its interactions are mostly in the cytoplasm. These results suggest that low doses of Cbl and very low doses of COS together kill Cbl-resistant ovarian carcinoma cells and ARHGEF6 signaling may have an instrumental role in induction of apoptosis in Cbl cos cells.

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Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Maiti

2009

Pharmacogenomics J

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“…Changes in intracellular ROS level due to glucose oxidase (GO) treatment were determined as described previously [28], [29]. Briefly, V79 cells were treated with increasing concentrations (10,20,40,60, 80 and 100 ng per ml) of GO for 1h in culture medium and excess GO was removed by washing cells in PBS.…”

Section: Measurement Of Intracellular Ros Levelmentioning

confidence: 99%

“…The alkaline single cell gel electrophoresis (Comet assay) was performed with minor modifications as described earlier [28]. Briefly, V79 and A549 cells were trypsinized and cell suspensions (10 3 cells/ml) in low melting point agarose (1% in PBS, pre-warmed to 37 C) were applied to CometSlides™ (Trevigen, Gaithersburg, MD).…”

Section: Comet Assaymentioning

confidence: 99%

Mutator phenotype of mammalian cells due to deficiency of NEIL1 DNA glycosylase, an oxidized base-specific repair enzyme

et al. 2008

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The recently characterized NEIL1 and NEIL2 are distinct from the previously characterized mammalian DNA glycosylases (OGG1 and NTH1) involved in repair of oxidized bases because of the NEILs' preference for excising base lesions from single-stranded DNA present in bubble and fork structures. OGG1 and NTH1 are active only with duplex DNA. This raises the possibility that NEILs function in the repair of base lesions during DNA replication and/or transcription. S-phasespecific activation of only NEIL1 suggests its preferential involvement in repair during DNA replication. Here we show that antisense oligonucleotides specific for human or Chinese hamster NEIL1 decreased in vivo NEIL1 levels by 70-80%, concomitant with increased oxidative damage in the genome. Moreover, NEIL1 downregulation enhanced spontaneous mutation in the HPRT locus by about 3-fold in both Chinese hamster V79 and human bronchial A549 cell lines. The mutant frequency was further enhanced (7-to 8-fold) under oxidative stress. The majority of both spontaneous and induced mutations occurred at A•T base pairs, indicating that oxidized A and/or T are NEIL1's preferred in vivo substrates. NEIL1 thus plays a distinct and important role in repairing endogenous and induced mutagenic oxidized bases, and hence in maintaining the functional integrity of mammalian genomes.

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Thermoresponsive Chlorambucil Derivatives for Tumour Targeting

Clavel¹,

Zava²,

Schmitt³

et al. 2011

Angewandte Chemie

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Wärme macht aktiv: Wirkstoffe, die bei 37 °C praktisch inaktiv sind, aber bei leicht erhöhter Temperatur aktiv werden, lassen sich durch das Anbringen thermoresponsiver Gruppen von Chlorambucil synthetisieren (siehe Bild; C grau, Cl grün, F gelb, H weiß, N blau, O rot). Diese Modifizierung sollte den gezielteren Einsatz zytotoxischer Substanzen ermöglichen und folglich deren Nebenwirkungen vermeiden.

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Reduced DNA double strand breaks in chlorambucil resistant cells are related to high DNA-PKcs activity and low oxidative stress

Cited by 59 publications

References 63 publications

Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Mutator phenotype of mammalian cells due to deficiency of NEIL1 DNA glycosylase, an oxidized base-specific repair enzyme

Thermoresponsive Chlorambucil Derivatives for Tumour Targeting

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