TY - JOUR
T1 - Interaction of mitoxantrone with abasic sites - DNA strand cleavage and inhibition of apurinic/apyrimidinic endonuclease 1, APE1
AU - Minko, Irina G.
AU - Moellmer, Samantha A.
AU - Luzadder, Michael M.
AU - Tomar, Rachana
AU - Stone, Michael P.
AU - McCullough, Amanda K.
AU - Stephen Lloyd, R.
N1 - Publisher Copyright:
© 2023 Elsevier B.V.
PY - 2024/1
Y1 - 2024/1
N2 - Mitoxantrone (1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]-anthracene-9,10-dione) is a clinically-relevant synthetic anthracenedione that functions as a topoisomerase II poison by trapping DNA double-strand break intermediates. Mitoxantrone binds to DNA via both stacking interactions with DNA bases and hydrogen bonding with the sugar-phosphate backbone. It has been shown that mitoxantrone inhibits apurinic/apyrimidinic (AP) endonuclease 1 (APE1)-catalyzed incision of DNA containing a tetrahydrofuran (THF) moiety and more recently, that mitoxantrone forms Schiff base conjugates at AP sites in DNA. 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.
AB - Mitoxantrone (1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]-anthracene-9,10-dione) is a clinically-relevant synthetic anthracenedione that functions as a topoisomerase II poison by trapping DNA double-strand break intermediates. Mitoxantrone binds to DNA via both stacking interactions with DNA bases and hydrogen bonding with the sugar-phosphate backbone. It has been shown that mitoxantrone inhibits apurinic/apyrimidinic (AP) endonuclease 1 (APE1)-catalyzed incision of DNA containing a tetrahydrofuran (THF) moiety and more recently, that mitoxantrone forms Schiff base conjugates at AP sites in DNA. 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.
KW - Anthracenediones
KW - Base Excision Repair
KW - DNA thermodynamics
KW - DNA-drug interactions
KW - Lyase activity
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U2 - 10.1016/j.dnarep.2023.103606
DO - 10.1016/j.dnarep.2023.103606
M3 - Article
C2 - 38039951
AN - SCOPUS:85178133062
SN - 1568-7864
VL - 133
JO - DNA Repair
JF - DNA Repair
M1 - 103606
ER -