Interactions of pixantrone with apurinic/apyrimidinic sites in DNA

Pixantrone and mitoxantrone are structurally related anticancer drugs which have been shown to generate covalent conjugates at apurinic/apyrimidinic (AP) sites in DNA. Mitoxantrone binding to AP sites induces DNA strand cleavage and inhibits the endonuclease activity of human AP endonuclease 1 (APE1). Here, pixantrone was demonstrated to have similar properties, but relative to mitoxantrone, it was significantly less potent in both DNA incision and APE1 inhibition. Consistent with these observations, pixantrone had ~ 15-fold lower affinity for DNA containing an AP site analogue, tetrahydrofuran, as measured by a Thiazole Orange (ThO) displacement assay.