Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both Topoisomerase II isoforms

Abstract

BackgroundThe 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.MethodsWe 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).ResultsDRZ 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.ConclusionsTaken 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.

Oxidative stress does not play a primary role in the toxicity induced with clinical doses of doxorubicin in myocardial H9c2 cells

“…The works carried out by Lyu et al suggested that proteasomal degradation of TOP2β induced by DXR abolishes DOX-mediated DNA damage in H9c2 cardiomyoblasts [ 66 ]. [ 68 ]. Although DXR mechanisms have not been thoroughly investigated here, our findings support that it is more likely that DXR cardioprotective effect on differentiated H9c2 cells is linked to its interference with DOX on TOP2-mediated DNA cleavage rather than through a metal ion-chelating activity.…”

Pharmacogenetics of Chemotherapy-Induced Cardiotoxicity

“…Interestingly, cardiomyocytes do not express topoisomerase IIα like tumor cells, but topoisomerase IIβ which can similarly complex with anthracyclines and result in cell death and decreased mitochondrial biogenesis [10, 11]. This is important because dexrozaxane is a cardioprotectant that has been shown to decrease incidence and severity of cardiotoxicity from anthracycline exposure [12–14] and acts through inhibition of both isomers of topoisomerase II as well as by chelating free iron and decreasing free radical generation [15–17]. …”

Current views on anthracycline cardiotoxicity

“…Dexrazoxane reduces the incidence of anthracyclineinduced HF by 80 % and is the only drug approved for its prevention [94]. A recent study demonstrates that dexrazoxane may prevent doxorubicin-induced DNA damage through depleting both topoisomerase II isoforms (Top IIa and b) [95]. Very recently, some investigators provided interesting experimental hints on the use of beta-blockers in the setting of anthracyclines and anti-HER2 treatments [96].…”