Abstract
Coadministration of the iron chelator dexrazoxane reduces by 80% the incidence of heart failure in cancer patients treated with anthracyclines. The clinical application of dexrazoxane is limited, however, because its ability to inhibit topoisomerase IIα (TOP2A) is feared to adversely affect anthracycline chemotherapy, which involves TOP2A-mediated generation of DNA double-strand breaks (DSB). Here, we investigated the apoptotic effects of dexrazoxane and the anthracycline doxorubicin, alone and in combination, in a tumor cell line with conditionally regulated expression of TOP2A. Each drug caused apoptosis that was only partly dependent on TOP2A. Unexpectedly, dexrazoxane was found to cause TOP2A depletion, thereby reducing the doxorubicin-induced accumulation of DSB. Despite this latter effect, dexrazoxane showed no adverse effect on doxorubicin-induced apoptosis. This could be explained by the TOP2A-independent apoptotic effects of each drug: those of doxorubicin included TOP2A-independent DSB formation and depletion of intracellular glutathione, whereas those of dexrazoxane were caspase independent. In conclusion, both doxorubicin and dexrazoxane induce apoptosis via TOP2A-dependent and TOP2A-independent mechanisms, the latter compensating for the reduction in cell killing due to dexrazoxane-induced TOP2A depletion. These observations suggest an explanation for the absence of adverse dexrazoxane effects on clinical responses to doxorubicin.
Highlights
Anthracyclines belong to the most successful drugs used in oncology because they are effective against a wide range of common cancers [1]
We wanted to characterize the contribution of TOP2A to apoptosis induced by doxorubicin and dexrazoxane
TOP2A-depleted and control cells were exposed to doxorubicin and dexrazoxane at concentrations corresponding to the range measured in blood of patients treated with either drug
Summary
Anthracyclines belong to the most successful drugs used in oncology because they are effective against a wide range of common cancers [1]. Considering the impressive cardioprotective effect of dexrazoxane, its coadministration with anthracyclines to cancer patients has been disappointingly limited. This is mostly due to the persisting fears that combining these drugs may adversely affect outcomes of cancer treatments. These fears have been refuted in several randomized clinical studies [3, 5], it is likely that dexrazoxane does interact with anthracyclines in cancer cells. The combined effects of dexrazoxane and anthracyclines have been previously tested in several cell and animal cancer models. No satisfactory explanation has been found for these disparate observations
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