Characterisation of cytotoxicity and DNA damage induced by the topoisomerase II-directed bisdioxopiperazine anti-cancer agent ICRF-187 (dexrazoxane) in yeast and mammalian cells

Jensen, Lars H.; Dejligbjerg, Marielle; Hansen, Lasse Tengbjerg; Grauslund, Morten; Jensen, Peter Buhl; Sehested, Maxwell

doi:10.1186/1471-2210-4-31

Cited by 17 publications

(3 citation statements)

References 64 publications

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“…Furthermore, Ku80- and DNA-PKcs-deficient Chinese hamster cell lines display a hypersensitive phenotype, as assessed by clonogenic survival. In close agreement with our data, it has been reported that the DNA-PKcs deficient V3-3 Chinese hamster cell line was hypersensitive to m-AMSA [44] .…”

Section: Discussionsupporting

confidence: 93%

“…Furthermore, BRCA2- and Rad51C-mutant Chinese hamster cells show hypersensitivity to the Top2 poisons. In agreement with our findings, it was reported an increased sensitivity to Top2 poisons of XRCC3-deficient Chinese hamster cells [44] , BRCA1- and BRCA2-mutant human tumoral cells [49] , and a middle sensitivity of rad54 −/− and rad52 −/− chicken DT40 cell lines [32] , [50] .…”

Section: Discussionsupporting

confidence: 93%

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Topoisomerase II-Mediated DNA Damage Is Differently Repaired during the Cell Cycle by Non-Homologous End Joining and Homologous Recombination

2010

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Topoisomerase II (Top2) is a nuclear enzyme involved in several metabolic processes of DNA. Chemotherapy agents that poison Top2 are known to induce persistent protein-mediated DNA double strand breaks (DSB). In this report, by using knock down experiments, we demonstrated that Top2α was largely responsible for the induction of γH2AX and cytotoxicity by the Top2 poisons idarubicin and etoposide in normal human cells. As DSB resulting from Top2 poisons-mediated damage may be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR), we aimed to analyze both DNA repair pathways. We found that DNA-PKcs was rapidly activated in human cells, as evidenced by autophosphorylation at serine 2056, following Top2-mediated DNA damage. The chemical inhibition of DNA-PKcs by wortmannin and vanillin resulted in an increased accumulation of DNA DSB, as evaluated by the comet assay. This was supported by a hypersensitive phenotype to Top2 poisons of Ku80- and DNA-PKcs- defective Chinese hamster cell lines. We also showed that Rad51 protein levels, Rad51 foci formation and sister chromatid exchanges were increased in human cells following Top2-mediated DNA damage. In support, BRCA2- and Rad51C- defective Chinese hamster cells displayed hypersensitivity to Top2 poisons. The analysis by immunofluorescence of the DNA DSB repair response in synchronized human cell cultures revealed activation of DNA-PKcs throughout the cell cycle and Rad51 foci formation in S and late S/G2 cells. Additionally, we found an increase of DNA-PKcs-mediated residual repair events, but not Rad51 residual foci, into micronucleated and apoptotic cells. Therefore, we conclude that in human cells both NHEJ and HR are required, with cell cycle stage specificity, for the repair of Top2-mediated reversible DNA damage. Moreover, NHEJ-mediated residual repair events are more frequently associated to irreversibly damaged cells.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Topoisomerase II-Mediated DNA Damage Is Differently Repaired during the Cell Cycle by Non-Homologous End Joining and Homologous Recombination

2010

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“…Cells with different single-gene depletion display distinctive sensitivity to chemotherapeutics [ 12 ]. Likewise, human non-small-cell lung cancer (NSCLC) H1299 (p53-null) cell is more sensitive to curcumin than A549 (p53-wt) cells [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to 8-Chloro-Adenosine

Yang

et al. 2018

IJMS

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Human lung cancer H1299 (p53-null) cells often display enhanced susceptibility to chemotherapeutics comparing to A549 (p53-wt) cells. However, little is known regarding to the association of DNA damage-response (DDR) pathway heterogeneity with drug sensitivity in these two cells. We investigated the DDR pathway differences between A549 and H1299 cells exposed to 8-chloro-adenosine (8-Cl-Ado), a potential anticancer drug that can induce DNA double-strand breaks (DSBs), and found that the hypersensitivity of H1299 cells to 8-Cl-Ado is associated with its DSB overaccumulation. The major causes of excessive DSBs in H1299 cells are as follows: First, defect of p53-p21 signal and phosphorylation of SMC1 increase S phase cells, where replication of DNA containing single-strand DNA break (SSB) produces more DSBs in H1299 cells. Second, p53 defect and no available induction of DNA repair protein p53R2 impair DNA repair activity in H1299 cells more severely than A549 cells. Third, cleavage of PARP-1 inhibits topoisomerase I and/or topoisomerase I-like activity of PARP-1, aggravates DNA DSBs and DNA repair mechanism impairment in H1299 cells. Together, DDR pathway heterogeneity of cancer cells is linked to cancer susceptibility to DNA damage-based chemotherapeutics, which may provide aid in design of chemotherapy strategy to improve treatment outcomes.

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DNA‐PKcs‐dependent NHEJ pathway supports the progression of topoisomerase II poison‐induced chromosome aberrant cells

Elguero

Campos-Nebel

González-Cid

2012

Environ and Mol Mutagen

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The role of DNA double strand break (DSB) repair pathways, non-homologous end joining (NHEJ), and homologous recombination (HR) was evaluated to prevent the chromosome instability induced by the topoisomerase II (Top2) poisons, idarubicin, and etoposide in Chinese hamster cell lines. XR-C1 (DNA-PKcs deficient) and V-C8 (BRCA2 deficient) showed higher sensitivity to increased concentrations of Top2 poisons compared with their normal counterparts, CHO9 and V79. Both proficient and deficient cells exhibited a marked DSB induction in all phases of the cell cycle. Additionally, deficient cells showed persistent DNA damage 24 hr post-treatment. Chromosomal aberrations increased in the first mitosis following Top2 poison-treatments in G1 or G2 in proficient and deficient cells. CHO9 and V79 demonstrated chromosome and chromatid exchanges following treatments in G1 and G2 phases, respectively. Deficient cells showed high frequencies of chromatid exchanges following treatments in G1 and G2. Simultaneously, we analyzed the micronuclei (MN) induction in interphase cells after treatments in G1, S, or G2 of the previous cell cycle. Both Top2 poisons induced an important increase in MN in CHO9, V79, and V-C8 cells. XR-C1 exhibited an increased MN frequency when cells were treated in G1 phase but not in S or G2. This MN reduction was due to a cell accumulation at G2/M and death in G2-treated cells. Our data suggest that NHEJ and HR operate differentially throughout the cell cycle to protect from Top2 poison-induced chromosome instability, and that DNA-PKcs-dependent NHEJ pathway allows the survival of chromosome damaged cells during S/G2 to the next interphase.

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Characterisation of cytotoxicity and DNA damage induced by the topoisomerase II-directed bisdioxopiperazine anti-cancer agent ICRF-187 (dexrazoxane) in yeast and mammalian cells

Cited by 17 publications

References 64 publications

Topoisomerase II-Mediated DNA Damage Is Differently Repaired during the Cell Cycle by Non-Homologous End Joining and Homologous Recombination

Topoisomerase II-Mediated DNA Damage Is Differently Repaired during the Cell Cycle by Non-Homologous End Joining and Homologous Recombination

DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to 8-Chloro-Adenosine

DNA‐PKcs‐dependent NHEJ pathway supports the progression of topoisomerase II poison‐induced chromosome aberrant cells

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