Figure 2.

Inhibition of type II topoisomerases by anthracyclines and dexrazoxane. To resolve tensions in supercoiled DNA, topoisomerase II induces a DNA double-strand break (DSB) to allow passage of another DNA strand, which is delivered from the open clamp (orange) (a). The DNA strand passes downwards through the DSB of the first strand and subsequently the open strand is resealed again (c). If anthracyclines bind at the region of interplay between the opened DNA and the topoisomerase II (b), the resealing of the DSB is disabled and a so-called cleavable complex consisting of anthracycline, DNA and topoisomerase persists until it is proteasomally degraded (d). Consequently, the opened DNA is left over containing a highly cytotoxic DSB that can trigger a pro-apoptotic DNA damage response. Binding of dexrazoxane to the ATPase domain of the topoisomerase keeps its clamp in a closed state (c), which prevents anthracycline binding as well as entrance into another enzymatic cycle (transition from the state illustrated under c to the state illustrated under a). A, anthracycline; DEX, dexrazoxane; DSB, DNA double-strand break; adapted from Lyu et al.⁵⁴ and Vejpongsa and Yeh³⁹