Topoisomerase IIβ–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.Abstract:
Doxorubicin is among the most effective and widely used anticancer drugs in the clinic. However, cardiotoxicity is one of the life-threatening side effects of doxorubicin-based therapy. Dexrazoxane (Zinecard, also known as ICRF-187) has been used in the clinic as a cardioprotectant against doxorubicin cardiotoxicity. The molecular basis for doxorubicin cardiotoxicity and the cardioprotective effect of dexrazoxane, however, is not fully understood. In the present study, we showed that dexrazoxane specifically abolished the DNA damage signal gamma-H2AX induced by doxorubicin, but not camptothecin or hydrogen peroxide, in H9C2 cardiomyocytes. Doxorubicin-induced DNA damage was also specifically abolished by the proteasome inhibitors bortezomib and MG132 and much reduced in top2beta(-/-) mouse embryonic fibroblasts (MEF) compared with TOP2beta(+/+) MEFs, suggesting the involvement of proteasome and DNA topoisomerase IIbeta (Top2beta). Furthermore, in addition to antagonizing Top2 cleavage complex formation, dexrazoxane also induced rapid degradation of Top2beta, which paralleled the reduction of doxorubicin-induced DNA damage. Together, our results suggest that dexrazoxane antagonizes doxorubicin-induced DNA damage through its interference with Top2beta, which could implicate Top2beta in doxorubicin cardiotoxicity. The specific involvement of proteasome and Top2beta in doxorubicin-induced DNA damage is consistent with a model in which proteasomal processing of doxorubicin-induced Top2beta-DNA covalent complexes exposes the Top2beta-concealed DNA double-strand breaks.read more
Citations
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Journal ArticleDOI
Targeting DNA topoisomerase II in cancer chemotherapy
TL;DR: These studies promise refined targeting of TOP2 as an effective anticancer strategy and the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy.
Journal ArticleDOI
Identification of the molecular basis of doxorubicin-induced cardiotoxicity
Sui Zhang,Xiaobing Liu,Xiaobing Liu,Tasneem Bawa-Khalfe,Long Sheng Lu,Yi Lisa Lyu,Leroy-Fong Liu,Edward T.H. Yeh,Edward T.H. Yeh +8 more
TL;DR: 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.
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Doxorubicin pathways: pharmacodynamics and adverse effects
Caroline F. Thorn,Connie Oshiro,Sharon Marsh,Tina Hernandez-Boussard,Howard L. McLeod,Teri E. Klein,Russ B. Altman +6 more
TL;DR: A brief background on the literature supporting the PharmGKB pathway about doxorubicin action, and a summary of this active area of research can be found in this paper.
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Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management.
TL;DR: The incidence of cardiotoxicity caused by commonly used chemotherapeutic agents as well as the pathogenesis, diagnosis, management, and prevention of these cardiovascular side effects are reviewed.
Journal ArticleDOI
Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation
Yoshihiko Ichikawa,Mohsen Ghanefar,Marina Bayeva,Rongxue Wu,Arineh Khechaduri,Sathyamangla V. Naga Prasad,R. Kannan Mutharasan,Tejaswitha J Naik,Hossein Ardehali +8 more
TL;DR: It is found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment, and that reducing mitochondrial iron levels protects against doxorbicin-induced cardiomyopathy.
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