Cells repair DNA damage via four main mechanisms, however, damage induced by
alkylators and oxidative damage is predominantly repaired by the
DNA base excision repair (BER) pathway. The
AP endonuclease, APE1, is one of the main
enzymes in the BER pathway. It is abundant in human cells and accounts for nearly all of the abasic site cleavage activity observed in cellular extracts. APE1 expression is elevated in a variety of
cancers and a high APE1 expression has been associated with poor outcome to
chemoradiotherapy. The small molecule
lucanthone has been shown to enhance the killing ability of ionizing radiation in cells and preliminary evidence suggests that
lucanthone may inhibit
AP endonuclease. Given the role APE1 plays in repairing oxidative and ionizing radiation DNA damage, the reports of
lucanthone as an ionizing radiation enhancer and the potential use of
lucanthone as an
AP endonuclease inhibitor, we examined whether
lucanthone could inhibit APE1
endonuclease activity. We report that
lucanthone inhibits the repair activity of APE1, but not its redox function or
exonuclease activity on mismatched
nucleotides.
Lucanthone also appears to inhibit
exonuclease III family members (APE1 and ExoIII), but not
endonuclease IV AP
endonucleases, nor bifunctional glycosylase/
lyases such as
endonuclease VIII or
formamidopyrimidine-DNA glycosylase (Fpg). Furthermore, the addition of
lucanthone inhibits APE1 repair activity from cellular extracts and enhances the cell killing effect of the laboratory
alkylating agent methyl methanesulfonate (MMS) and the clinically relevant agent
temozolomide (TMZ). Given these initial findings, it would be of interest to further develop
lucanthone as an APE1 inhibitor through the use of structure-function studies as a means of enhancing the sensitization of
tumors to chemotherapeutic agents.