Topoisomerase II beta levels are a determinant of melphalan-induced DNA crosslinks and sensitivity to cell death

2006 ◽  
Vol 72 (1) ◽  
pp. 11-18 ◽  
Author(s):  
M. Emmons ◽  
D. Boulware ◽  
D.M. Sullivan ◽  
L.A. Hazlehurst
Keyword(s):  
Cell Death ◽  
Topoisomerase Ii ◽  
Dna Crosslinks ◽  
Topoisomerase Ii Beta

scholarly journals The role of topoisomerase II beta on breakage and proximity of RUNX1 to partner alleles RUNX1T1 and EVI1

2013 ◽  
Vol 53 (2) ◽  
pp. 117-128 ◽  
Author(s):  
Kayleigh A. Smith ◽  
Ian G. Cowell ◽  
Yanming Zhang ◽  
Zbyslaw Sondka ◽  
Caroline A. Austin
Keyword(s):  
Topoisomerase Ii ◽  
Topoisomerase Ii Beta

Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation

2021 ◽  
Author(s):  
Eduard Jirkovský ◽  
Anna Jirkovská ◽  
Hana Bavlovič-Piskáčková ◽  
Veronika Skalická ◽  
Zuzana Pokorná ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Topoisomerase Ii ◽  
Left Ventricular ◽  
Functional Markers ◽  
Metal Chelation ◽  
Anthracycline Cardiotoxicity ◽  
Ventricular Cardiomyocytes ◽  
Cardioprotective Effects ◽  
Topoisomerase Ii Beta

Background: Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)—the only drug approved for its prevention—has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept. Methods: Pharmacokinetically guided study of the cardioprotective effects of clinically used DEX and its chelating metabolite ADR-925 (administered exogenously) was performed together with mechanistic experiments. The cardiotoxicity was induced by daunorubicin in neonatal ventricular cardiomyocytes in vitro and in a chronic rabbit model in vivo (n=50). Results: Intracellular concentrations of ADR-925 in neonatal ventricular cardiomyocytes and rabbit hearts after treatment with exogenous ADR-925 were similar or exceeded those observed after treatment with the parent DEX. However, ADR-925 did not protect neonatal ventricular cardiomyocytes against anthracycline toxicity, whereas DEX exhibited significant protective effects (10–100 µmol/L; P <0.001). Unlike DEX, ADR-925 also had no significant impact on daunorubicin-induced mortality, blood congestion, and biochemical and functional markers of cardiac dysfunction in vivo (eg, end point left ventricular fractional shortening was 32.3±14.7%, 33.5±4.8%, 42.7±1.0%, and 41.5±1.1% for the daunorubicin, ADR-925 [120 mg/kg]+daunorubicin, DEX [60 mg/kg]+daunorubicin, and control groups, respectively; P <0.05). DEX, but not ADR-925, inhibited and depleted TOP2B and prevented daunorubicin-induced genotoxic damage. TOP2B dependency of the cardioprotective effects was probed and supported by experiments with diastereomers of a new DEX derivative. Conclusions: This study strongly supports a new mechanistic paradigm that attributes clinically effective cardioprotection against anthracycline cardiotoxicity to interactions with TOP2B but not metal chelation and protection against direct oxidative damage.

Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death

2012 ◽  
Vol 132 (10) ◽  
pp. 2248-2257 ◽  
Author(s):  
Laura Conradt ◽  
Annika Henrich ◽  
Matthias Wirth ◽  
Maximilian Reichert ◽  
Marina Lesina ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Cancer Cell ◽  
Topoisomerase Ii ◽  
Pancreatic Cancer Cell ◽  
Topoisomerase Ii Inhibitors ◽  
Cancer Cell Death

Regulation by survivin of cancer cell death induced by F14512, a polyamine-containing inhibitor of DNA topoisomerase II

APOPTOSIS ◽  
2011 ◽  
Vol 17 (4) ◽  
pp. 364-376 ◽  
Author(s):  
Caroline Ballot ◽  
Manel Jendoubi ◽  
Jérome Kluza ◽  
Aurélie Jonneaux ◽  
William Laine ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Cancer Cell Death

scholarly journals Canonical non-homologous end-joining promotes genome mutagenesis and translocations induced by transcription-associated DNA topoisomerase 2 activity

2020 ◽  
Vol 48 (16) ◽  
pp. 9147-9160
Author(s):  
Joaquín Olmedo-Pelayo ◽  
Diana Rubio-Contreras ◽  
Fernando Gómez-Herreros
Keyword(s):  
Cell Death ◽  
Topoisomerase Ii ◽  
Genome Instability ◽  
Metabolic Enzyme ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Dna Topoisomerase ◽  
Transient Complex ◽  
Topoisomerase 2 ◽  
Non Homologous End Joining

Abstract DNA topoisomerase II (TOP2) is a major DNA metabolic enzyme, with important roles in replication, transcription, chromosome segregation and spatial organisation of the genome. TOP2 is the target of a class of anticancer drugs that poison the DNA-TOP2 transient complex to generate TOP2-linked DNA double-strand breaks (DSBs). The accumulation of DSBs kills tumour cells but can also result in genome instability. The way in which topoisomerase activity contributes to transcription remains unclear. In this work we have investigated how transcription contributes to TOP2-dependent DSB formation, genome instability and cell death. Our results demonstrate that gene transcription is an important source of abortive TOP2 activity. However, transcription does not contribute significantly to apoptosis or cell death promoted by TOP2-induced DSBs. On the contrary: transcription-dependent breaks greatly contribute to deleterious mutations and translocations, and can promote oncogenic rearrangements. Importantly, we show that TOP2-induced genome instability is mediated by mutagenic canonical non-homologous end joining whereas homologous recombination protects cells against these insults. Collectively, these results uncover mechanisms behind deleterious effects of TOP2 abortive activity during transcription, with relevant implications for chemotherapy.

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