Comparison of Different Iron Chelators as Protective Agents Against Acute Doxorubicin-induced Cardiotoxicity

Abstract

Doxorubicin (Dox) is a widely used antineoplastic agent. Irreversible cardiomyopathy is a serious and dose-limiting side effect after chronic administration. The iron chelating bispiperazinedione ICRF-187 is currently the only drug which affords protection against Dox-induced cardiotoxicity. To compare the protective value of structurally unrelated iron chelators, isolated mice atria were exposed to Dox (30 μM) and either the hydroxamate desferrioxamine (DFO, 200 and 500 μM), EDTA (200 μM) or the hydroxypyridones CP44 (200 μM), CP51 (200 μM), and CP93 (200 μM) and ICRF-187 (200 and 500 μM). The nitroxide TEMPO (5 mM) lacks iron chelating properties but was used to prevent redox cycling or iron and scavenge superoxide. All iron chelators, except EDTA, CP93 and CP44, were modestly protective against a Dox-induced decrease in contractile force. As a single agent the hydroxypyridones decreased atrial contractile force. At a concentration of 200 μM, DFO was the most effective protector of the chelators tested. However, this effect disappeared when a concentration of 500 μM was used. This in contrast to ICRF-187 for which a concentration-dependent inhibition of Dox-induced decrease in contractile force was observed. TEMPO exerted a biphasic response consisting of a two-fold increase in contractile force, followed by a decrease in force and irregular contractions. In this model TEMPO lacked any perspective as a cardioprotectant. We conclude that at 200 μM, DFO was the most effective agent to afford protection against Dox-mediated atrial malfunction. However, at 500 μM, DFO was not effective whereas ICRF-187 afforded partial protection. Hydroxipyridones were found to be of limited value because of a negative inotropic effect on the isolated atria.