Interaction of mitoxantrone with abasic sites - DNA strand cleavage and inhibition of apurinic/apyrimidinic endonuclease 1, APE1

In this study, mitoxantrone-mediated inhibition of APE1 at THF sites was shown to be consistent with preferential binding to, and thermal stabilization of DNA containing a THF site as compared to non-damaged DNA. Investigations into the properties of mitoxantrone at AP and 3' α,β-unsaturated aldehyde sites demonstrated that in addition to being a potent inhibitor of APE1 at these biologically-relevant substrates (∼ 0.5 μM IC50 on AP site-containing DNA), mitoxantrone also incised AP site-containing DNA by catalyzing β- and β/δ-elimination reactions. The efficiency of these reactions to generate the 3' α,β-unsaturated aldehyde and 3' phosphate products was modulated by DNA structure. Although these cell-free reactions revealed that mitoxantrone can generate 3' phosphates, cells lacking polynucleotide kinase phosphatase did not show increased sensitivity to mitoxantrone treatment. Consistent with its ability to inhibit APE1 activity on DNAs containing either an AP site or a 3' α,β-unsaturated aldehyde, combined exposures to clinically-relevant concentrations of mitoxantrone and a small molecule APE1 inhibitor revealed additive cytotoxicity. These data suggest that in a cellular context, mitoxantrone may interfere with APE1 DNA repair functions.PMID:38039951 | DOI:10.1016/j.dnarep.2023.103606
Source: DNA Repair - Category: Genetics & Stem Cells Authors: Source Type: research