DNA Repair Enzymes Tyrosyl-DNA Phosphodiesterases 1 and 2 Inhibitors Based on Usnic Acid as Potential Anticancer Agents

Alexandra L. Zakharenko; Nadezhda S. Dyrkheeva; Olga A. Luzina; Aleksander S. Filimonov; Evgenii S. Mozhaitsev; Anastasia A. Malakhova; Sergey P. Medvedev; Suren M. Zakian; Nariman F. Salakhutdinov; Olga I. Lavrik

doi:10.20944/preprints202308.0880.v1

A peer-reviewed article of this Preprint also exists.

Zakharenko, A.L.; Dyrkheeva, N.S.; Luzina, O.A.; Filimonov, A.S.; Mozhaitsev, E.S.; Malakhova, A.A.; Medvedev, S.P.; Zakian, S.M.; Salakhutdinov, N.F.; Lavrik, O.I. Usnic Acid Derivatives Inhibit DNA Repair Enzymes Tyrosyl-DNA Phosphodiesterases 1 and 2 and Act as Potential Anticancer Agents. Genes 2023, 14, 1931. Zakharenko, A.L.; Dyrkheeva, N.S.; Luzina, O.A.; Filimonov, A.S.; Mozhaitsev, E.S.; Malakhova, A.A.; Medvedev, S.P.; Zakian, S.M.; Salakhutdinov, N.F.; Lavrik, O.I. Usnic Acid Derivatives Inhibit DNA Repair Enzymes Tyrosyl-DNA Phosphodiesterases 1 and 2 and Act as Potential Anticancer Agents. Genes 2023, 14, 1931.

Abstract

Tdp1 and Tdp2 are DNA repair enzymes that repair DNA damages caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reasons of resistance to such widely used drugs as topotecan and etoposide. In the present work, we found compounds capable of inhibiting both enzymes among derivatives of (-)-usnic acid. Both (+)- and (-)-enantiomers of compounds act equally effectively against Tdp1, and only (-)-enantiomers inhibited Tdp2. Surprisingly, the compounds protect HEK293FT wild type cells from the cytotoxic effect of etoposide but potentiate it against Tdp2 knockout cells. We assume that the sensitizing effect of the compounds in the absence of Tdp2 is associated with effective inhibition of Tdp1, which could take over the functions of Tdp2.

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DNA Repair Enzymes Tyrosyl-DNA Phosphodiesterases 1 and 2 Inhibitors Based on Usnic Acid as Potential Anticancer Agents

Abstract

Keywords

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