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Effect of Usnic Acid-Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitor Used as Monotherapy or in Combination with Olaparib on Transplanted Tumors In Vivo

  • SYSTEMIC PHARMACOLOGY AND CREATION OF NEW MEDICAL TECHNOLOGIES
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Abstract

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme that removes various adducts from the 3' end of DNA. Such adducts are formed by enzymes that introduce single-strand breaks in DNA during catalysis (for example, topoisomerase 1) and a number of anticancer drugs with different mechanisms of action. Poly(ADP-ribose) polymerase 1 (PARP1) is an enzyme that catalyzes posttranslational modification (PARylation) of various targets and thus controls many cell processes, including DNA repair. Tdp1 is a PARP1 target, and its PARylation attracts Tdp1 to the site of DNA damage. Olaparib is a PARP1 inhibitor used in clinical practice to treat homologous recombination-deficient tumors. Olaparib inhibits PARylation and, therefore, DNA repair. The Tdp1 inhibitor OL7-43 was used in combination with olaparib to increase the antitumor effect of the latter. Olaparib cytotoxicity was found to increase in the presence of OL7-43 in vitro. OL7-43 did not exert a sensitizing effect, but showed its own antitumor and antimetastatic effects in Lewis and Krebs-2 carcinoma models.

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ACKNOWLEDGMENTS

We are grateful to A.G. Mozhnaya for advice on working with laboratory animals.

Funding

This work was supported by the Russian Science Foundation (project no. 21-14-00105; Т.Е. Kornienko, N.S. Dyrkheeva, А.L. Zakharenko, А.S. Filimonov, А.А. Chepanova, N.А. Popova, and V.P. Nikolin) and a state contract with the Institute of Chemical Biology and Fundamental Medicine (project no. 121031300041-4; Е.S. Ilina, О.D. Zakharova, and О.I. Lavrik).

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Authors and Affiliations

  1. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, 630090, Novosibirsk, Russia

    T. E. Kornienko, A. L. Zakharenko, E. S. Ilina, A. A. Chepanova, O. D. Zakharova & N. S. Dyrkheeva

  2. Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, 630090, Novosibirsk, Russia

    N. A. Popova & V. P. Nikolin

  3. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, 630090, Novosibirsk, Russia

    A. S. Filimonov, O. A. Luzina, N. F. Salakhutdinov & O. I. Lavrik

  4. Novosibirsk State University, 630090, Novosibirsk, Russia

    E. S. Ilina, N. A. Popova, N. F. Salakhutdinov & O. I. Lavrik

Authors
  1. T. E. Kornienko
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  2. A. L. Zakharenko
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  3. E. S. Ilina
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  4. A. A. Chepanova
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  5. O. D. Zakharova
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  6. N. S. Dyrkheeva
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  7. N. A. Popova
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  8. V. P. Nikolin
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  9. A. S. Filimonov
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  10. O. A. Luzina
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  11. N. F. Salakhutdinov
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  12. O. I. Lavrik
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Corresponding author

Correspondence to O. I. Lavrik.

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Conflict of interests. The authors declare that they have no conflict of interest.

Statement on the welfare of animals. All procedures with mice were carried out in compliance with international guidelines for animal research (European Council Directive 86/609 EEC).

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Translated by T. Tkacheva

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Kornienko, T.E., Zakharenko, A.L., Ilina, E.S. et al. Effect of Usnic Acid-Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitor Used as Monotherapy or in Combination with Olaparib on Transplanted Tumors In Vivo. Mol Biol 57, 214–224 (2023). https://doi.org/10.1134/S0026893323020127

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