Dexrazoxane protects the heart from acute doxorubicin‐induced QT prolongation: a key role forI_Ks

Abstract

Introduction: Doxorubicin, an anthracycline widely used in the treatment of a broad range of tumours, causes acute QT prolongation. Dexrazoxane has been shown to prevent the QT prolongation induced by another anthracycline, epirubicin, but has not yet been reported to prevent that induced by doxorubicin. Thus, the present study was designed to test whether the acute QT effects induced by doxorubicin could be blocked by dexrazoxane and to explore the mechanism. Results were compared with those obtained with a reference human ether-a-go-go (hERG) channel blocker, moxifloxacin. Methods: The effects of moxifloxacin (100 mM) and doxorubicin (30 mM), with or without dexrazoxane (from 3 to 30 mM), have been evaluated on the QTc interval in guinea-pig isolated hearts and on IKr (rapid component of the delayed rectifier current) and IKs (slow component of the delayed rectifier current) currents stably expressed in human embryonic kidney 293 cells. Results: Moxifloxacin (100 mM), a potent hERG blocker, prolonged QTc by 22%, and this effect was not prevented by dexrazoxane. Doxorubicin (30 mM) also prolonged QTc by 13%, did not significantly block hERG channels and specifically inhibited IKs (IC50: 4.78 mM). Dexrazoxane significantly reduced the doxorubicin-induced QTc prolongation and prevented doxorubicin-induced inhibition of IKs. Conclusion and implications: Doxorubicin acutely prolonged the QT interval in guinea-pig heart by selective IKs blockade. This effect was prevented by dexrazoxane. This result is important because it illustrates the danger of neglecting IKs in favour of hERG screening alone, for early preclinical testing for possible induction of torsade de pointes.

Comparative Study of the Protective Effect of Metformin and Sitagliptin against Doxorubicin-Induced Cardiotoxicity in Rats

“…The results of the present study are in agreement with Xu [21] who showed weight loss, [22] who demonstrated significant reduction in systolic blood pressure [23] Different cellular mechanisms may explain doxorubicin-induced cardiac toxicity as increase intracellular iron accumulation causing increased oxidative stress [29], preventing the repair of damaged DNA strands [30], changes in vascular endothelium-derived vasoactive mediators (endothelin-1 and cardiac nitric oxide) [31] and alteration of cardiac-specific gene expression including struc tural, metabolic and enzyme activities [32].…”

Cardioprotective Effect of Grape Seed Extract on Chronic Doxorubicin-Induced Cardiac Toxicity in Wistar Rats

“…61 In addition, recent studies demonstrated the bioavailability of grape seed proanthocyanidins to the target organs exhibiting a superior protection against oxidative DNA damage and oxidative stress relative to vitamin C, E and β-carotene. 12 In support of our findings, it has been reported that various chemical compounds such as carvedilol, 62 rosmarinic acid, 63 dexrazoxane 64,65 as well as herbal agents including GSE, 18,39 saffron extract 66 and garlic extract 67 found to potentially be protective against DOX-induced cardiotoxicity. Based on reported studies GSE produces protective effect by several mechanisms including antioxidant effect, 68,69 decreasing the number of apoptotic cells, 70 prevention of DNA fragmentation, 15,71 regulation of the expression levels of the pro-apoptotic protein Bax-alpha, 72 increasing antiapoptotic protein Bcl-2 73 and inhibition of apoptotic signaling pathways.…”

Mechanisms and management of doxorubicin cardiotoxicity

“…Doxorubicin and its metabolites can disrupt the Fe-S cluster of cytoplasmic aconitase and inhibit IRP-1, whose role it is to adapt the levels of cellular iron appropriate to the metabolic needs of the cell. It has been suggested that doxorubicin-mediated intracellular iron accumulation causing increased oxidative stress is a major aspect of doxorubicin toxicity and that iron chelators are highly effective in reducing doxorubicin-induced cardiotoxicity [13,14]. Interestingly, patients harboring gene mutations in hereditary hemochromatosis (HH) show increased susceptibility to doxorubicin cardiotoxicity and exacerbated iron metabolism [15].…”

“…Of note, dexrazoxane appears to provide long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children [138]. The underlying mechanisms include iron chelation [11,14,139], protecting the heart from acute doxorubicin-induced QT prolongation via I(Ks) [13], and upregulation of Akt and Erk phosphorylation pathways [14].…”