Topoisomerase 2β: A Promising Molecular Target for Primary Prevention of Anthracycline‐Induced Cardiotoxicity

@article{Vejpongsa2014Topoisomerase2A,
  title={Topoisomerase 2$\beta$: A Promising Molecular Target for Primary Prevention of Anthracycline‐Induced Cardiotoxicity},
  author={Pimprapa Vejpongsa and Eth Yeh},
  journal={Clinical Pharmacology \& Therapeutics},
  year={2014},
  volume={95}
}
  • P. Vejpongsa, Eth Yeh
  • Published 19 December 2013
  • Chemistry, Biology, Medicine
  • Clinical Pharmacology & Therapeutics
Anthracyclines are powerful chemotherapy agents that are still widely used today. However, their clinical use is limited by the development of dose‐dependent cardiotoxicity. Recently, we showed that topoisomerase 2β (Top2β) is required for anthracycline to induce DNA double‐strand breaks and changes in the transcriptome, leading to mitochondrial dysfunction and generation of reactive oxygen species. Furthermore, deleting Top2β from cardiomyocytes prevented the development of anthracycline… 
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References

SHOWING 1-10 OF 84 REFERENCES
Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane.
TLDR
It is shown that dexrazoxane specifically abolished the DNA damage signal gamma-H2AX induced by doxorubicin, but not camptothecin or hydrogen peroxide, in H9C2 cardiomyocytes, and this results suggest that dex Razoxane antagonizesDoxorubsicin-induced DNA damage through its interference with Top2beta, which could implicate Top2 beta indoxorUBicin cardiotoxicity.
Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies
TLDR
It is shown here that VP-16-induced carcinogenesis involves mainly the β rather than the α isozyme of Top2, suggesting the importance of developing Top2α-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.
Protecting against anthracycline‐induced myocardial damage: a review of the most promising strategies
TLDR
The most promising current strategies to limit or prevent anthracycline‐induced cardiotoxicity, as well as possible strategies to prevent existing cardiomyopathy from worsening are summarised.
NK314, a Topoisomerase II Inhibitor That Specifically Targets the α Isoform*
TLDR
It is shown that NK314, a novel synthetic benzo[c]phenanthridine alkaloid, targets Top2α and not Top2β in vivo, and that a series of human knock-out cell lines are useful in assessing DNA damage and repair induced by potential topoisomerase-targeting agents.
Identification of the molecular basis of doxorubicin-induced cardiotoxicity
TLDR
Cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation.
Acute Doxorubicin Cardiotoxicity Is Associated With p53-Induced Inhibition of the Mammalian Target of Rapamycin Pathway
TLDR
It is suggested that doxorubicin treatment induces acute cardiac dysfunction and reduces cardiac mass via p53-dependent inhibition of mTOR signaling and that loss of myocardial mass, and not cardiomyocyte apoptosis, is the major contributor to acute doxorbicin cardiotoxicity.
Topoisomerase II beta expression level correlates with doxorubicin-induced apoptosis in peripheral blood cells
TLDR
The expression level of topo II beta is intra- and inter-individually variable, and may in part determine the apoptotic response to doxorubicin and other anthracyclines.
Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy.
TLDR
Monitoring IRP activities in H9c2 rat embryo cardiomyocytes exposed to DOX or to analogues revealed that IRP-2 was inactivated only by ROS, serving guidelines for designing anthracyclines that spare iron homeostasis and induce less severe cardiotoxicity.
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