Selective Antitumor Activity and Photocytotoxicity of Glutathione-Activated Abasic Site Trapping Agents

Abasic (AP) sites are one of the most commonDNA lesions in cells. Aldehyde-reactive alkoxyamines capture APsites and block the activity of APE1, the enzyme responsible forinitiating their repair. Blocking the APE1 repair of AP sites leads tocell death, and it is an actively investigated approach for treatingcancer. However, unselective AP site capture in different cellsproduces side effects and limits the application of alkoxyamines inchemotherapy. Herein we take advantage of the higher glutathione(GSH) concentration in cancer cells over normal cells to developGSH-inducible agents that selectively kill cancer cells. 2,4-Dinitrobenzenesulfonamide caged coumarin-based alkoxyamines1and2are selectively revealed by GSH to release SO2andfluorescent coumarin-based alkoxyamines3and4that trap APsites in cells. GSH-directed AP site trapping and SO2release result in selective cytotoxicity (defined as IC50WI38/IC50H1299)against H1299 lung cancer cells over normal WI38 lung cells, ranging from 1.8 to 2.8 for1and2. The alkylating agentmethylmethanesulfonate (MMS) promotes the formation of AP sites in cells and enhances the cytotoxicity of agent1in a dose-dependent way. Moreover, the comet assay and gamma H2AX assay suggest that AP adducts form a highly toxic DNA interstrand cross-link(ICL) upon photolysis, leading to further cell death. DNAflow cytometric analysis showed that1promoted cell apoptosis in theearly stage and induced G2/M phase cell-cycle arrest. The 2,4-dinitrobenzenesulfonamide-caged alkoxyamines exhibited selectiveantitumor activity and photocytotoxicity in cancer cells, illuminating their potential as GSH-directed chemotherapeutic agents.

Automated summary

This study developed a drug that selectively kills cancer cells by taking advantage of the difference in glutathione (GSH) concentration. The drug captures and blocks the repair of AP sites in DNA, leading to cell death. Additionally, the drug exhibits selective antitumor activity and photocytotoxicity.