title: Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both topoisomerase II isoforms.
abstract: BACKGROUND
  The bisdioxopiperazine dexrazoxane (DRZ) prevents anthracycline-induced heart failure, but its clinical use is limited by uncertain cardioprotective mechanism and by concerns of interference with cancer response to anthracyclines and of long-term safety.
  
  
  METHODS
  We investigated the effects of DRZ on the stability of topoisomerases IIα (TOP2A) and IIβ (TOP2B) and on the DNA damage generated by poisoning these enzymes by the anthracycline doxorubicin (DOX).
  
  
  RESULTS
  DRZ given i.p. transiently depleted in mice the predominant cardiac isoform Top2b. The depletion was also seen in H9C2 cardiomyocytes and it was attenuated by mutating the bisdioxopiperazine binding site of TOP2B. Consistently, the accumulation of DOX-induced DNA double strand breaks (DSB) by wild-type, although not by mutant TOP2B, was reduced by DRZ. In contrast, the DRZ analogue ICRF-161, which is capable of iron chelation but not of TOP2B binding and cardiac protection, did not deplete TOP2B and did not prevent the accumulation of DOX-induced DSB. TOP2A, re-expressed in cultured cardiomyocytes by fresh serum, was depleted by DRZ along with TOP2B. DRZ depleted TOP2A also from fibrosarcoma-derived cells, but not from lung cancer-derived and human embryo-derived cells. DRZ-mediated TOP2A depletion reduced the accumulation of DOX-induced DSB.
  
  
  CONCLUSIONS
  Taken together, our data support a model of anthracycline-induced heart failure caused by TOP2B-mediated DSB and of its prevention by DRZ via TOP2B degradation rather than via iron chelation. The depletion of TOP2B and TOP2A suggests an explanation for the reported DRZ interference with cancer response to anthracyclines and for DRZ side-effects.
authors.affiliation: Institute of Pharmacology, Medical Center of the University Mainz, Obere Zahlbacher Str, 67, D-55131 Mainz, Germany. deng@uni-mainz.de.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Deng
authors.forename: Tiandong
authors.initials: T
authors.lastname: Yan
authors.forename: Cathleen
authors.initials: C
authors.lastname: Jendrny
authors.forename: Andrea
authors.initials: A
authors.lastname: Nemecek
authors.forename: Mladen
authors.initials: M
authors.lastname: Vincetic
authors.forename: Ute
authors.initials: U
authors.lastname: Gödtel-Armbrust
authors.forename: Leszek
authors.initials: L
authors.lastname: Wojnowski
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D064730:Dexrazoxane / Q000494:pharmacology*; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes; D051379:Mice; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D020011:Protective Agents / Q000494:pharmacology; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D000075223:Poly-ADP-Ribose Binding Proteins; D020011:Protective Agents; D059005:Topoisomerase II Inhibitors; D064730:Dexrazoxane; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618814:TOP2B protein, human; C000618812:Top2a protein, mouse; C000618815:Top2b protein, mouse