Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane.
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.
Lyu
Yi Lisa
YL
Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635, USA. lyuyi@umdnj.edu
Kerrigan
John E
JE
Lin
Chao-Po
CP
Azarova
Anna M
AM
Tsai
Yuan-Chin
YC
Ban
Yi
Y
Liu
Leroy F
LF
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors / Q000633:toxicity; D053903:DNA Breaks, Double-Stranded; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004347:Drug Interactions; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011487:Protein Conformation; D011929:Razoxane / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D061988:Proteasome Inhibitors; D059005:Topoisomerase II Inhibitors; D011929:Razoxane; D004317:Doxorubicin; D046988:Proteasome Endopeptidase Complex; D004250:DNA Topoisomerases, Type II