Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for IKs

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 mu M) and doxorubicin (30 mu M), with or without dexrazoxane (from 3 to 30 mu M), have been evaluated on the QTc interval in guinea-pig isolated hearts and on I-Kr (rapid component of the delayed rectifier current) and I-Ks (slow component of the delayed rectifier current) currents stably expressed in human embryonic kidney 293 cells. Results: Moxifloxacin (100 mu M), a potent hERG blocker, prolonged QTc by 22%, and this effect was not prevented by dexrazoxane. Doxorubicin (30 mu M) also prolonged QTc by 13%, did not significantly block hERG channels and specifically inhibited I-Ks (IC50: 4.78 mu M). Dexrazoxane significantly reduced the doxorubicin-induced QTc prolongation and prevented doxorubicin-induced inhibition of I-Ks. Conclusion and implications: Doxorubicin acutely prolonged the QT interval in guinea-pig heart by selective I-Ks blockade. This effect was prevented by dexrazoxane. This result is important because it illustrates the danger of neglecting I-Ks in favour of hERG screening alone, for early preclinical testing for possible induction of torsade de pointes.British Journal of Pharmacology (2010) 159, 93-101; doi:10.1111/j.1476-5381.2009.00371.x; published online 24 August 2009