The Role of Topoisomerase IIβ in the Mechanisms of Action of the Doxorubicin Cardioprotective Agent Dexrazoxane.

Abstract

Dexrazoxane is clinically used to reduce doxorubicin cardiotoxicity and anthracycline-induced extravasation injury. Dexrazoxane is a strong catalytic inhibitor of topoisomerase II. It can also undergo metabolism to form an iron-binding analog of EDTA. Dexrazoxane was originally thought to act by reducing iron-dependent doxorubicin-based oxidative stress. However, a competing hypothesis posits that dexrazoxane may be protective through its ability to inhibit and reduce topoisomerase IIβ protein levels in the heart. A primary neonatal rat myocyte model was used to study the mechanism by which dexrazoxane protects against doxorubicin-induced myocyte damage. This study characterized the kinetics of the rapid and nearly complete dexrazoxane-induced loss of topoisomerase IIβ protein from neonatal rat cardiac myocytes. Immunofluorescent staining of attached myocytes for topoisomerase IIβ revealed that most of the topoisomerase IIβ was localized to the nucleus, although it was also present in the cytoplasm. Dexrazoxane treatment resulted in an almost complete reduction of topoisomerase IIβ in the nucleus and a lesser reduction in the cytoplasm. The recovery of topoisomerase IIβ levels after a pulse topoisomerase IIβ inhibitory concentration of dexrazoxane occurred slowly, with partial recovery only occurring after 24h. The ability of dexrazoxane to reduce doxorubicin-induced damage to myocytes was greatest when topoisomerase IIβ levels were at their lowest.