Influence of Usnic Acid Derivative (Tyrosyl-DNA Phosphodiesterase 1 Inhibitor) on Transplanted Tumors in vivo as a Monotherapy and in Combination with Olaparib

Т. Е. Kornienko; Корниенко Т. Е.; N. F. Salakhutdinov; Салахутдинов Н. Ф.; О. А. Luzina; Лузина О. А.; А. S. Filimonov; Филимонов А. С.; V. P. Nikolin; Николин В. П.; N. А. Popova; Попова Н. А.; N. S. Dyrkheeva; Дырхеева Н. С.; О. D. Zakharova; Захарова О. Д.; А. А. Chepanova; Чепанова А. А.; Е. S. Ilina; Ильина Е. С.; А. L. Zakharenko; Захаренко А. Л.; О. I. Lavrik; Лаврик О. И.

doi:10.31857/S0026898423020143

Influence of Usnic Acid Derivative (Tyrosyl-DNA Phosphodiesterase 1 Inhibitor) on Transplanted Tumors in vivo as a Monotherapy and in Combination with Olaparib

Authors: Kornienko Т.Е.¹, Salakhutdinov N.F.²^,3, Luzina О.А.², Filimonov А.S.², Nikolin V.P.⁴, Popova N.А.⁴^,3, Dyrkheeva N.S.¹, Zakharova О.D.¹, Chepanova А.А.¹, Ilina Е.S.¹^,3, Zakharenko А.L.¹, Lavrik О.I.¹^,3
Affiliations:
1. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences
2. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences
3. Novosibirsk State University
4. Federal Research Centre Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences
Issue: Vol 57, No 2 (2023)
Pages: 220-231
Section: СИСТЕМНАЯ ФАРМАКОЛОГИЯ И СОЗДАНИЕ НОВЫХ МЕДИЦИНСКИХ ТЕХНОЛОГИЙ
URL: https://innoscience.ru/0026-8984/article/view/655436
DOI: https://doi.org/10.31857/S0026898423020143
EDN: https://elibrary.ru/EFXISX
ID: 655436

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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 damage is formed, for example, under the action of enzymes that introduce single-strand breaks in DNA during catalysis (for example, topoisomerase 1), as well as a number of anticancer drugs with different mechanisms of action. Poly(ADP-ribose) polymerase 1 (PARP1) is an enzyme that catalyzes the post-translational modification of various targets (PARylation), and with its help controls many processes in the cell, including DNA repair. The target of PARP1 is also Tdp1, whose PARylation attracts Tdp1 to the site of DNA damage. Olaparib is a PARP1 inhibitor used in clinical practice to treat homologous recombination deficient tumors. The main mechanism of action of olaparib is to obstruction of PARylation and thus DNA repair. In this study, we used the Tdp1 inhibitor OL7-43 in combination with olaparib to increase the antitumor effect of the latter. Despite the increase in cytotoxicity of olaparib in the presence of OL7-43 in vitro, we did not find a sensitizing effect of this compound in the Lewis and Krebs-2 carcinoma models, but it showed its own antitumor and antimetastatic effects.

Keywords

tyrosyl-DNA phosphodiesterase 1, Tdp1 inhibitor, olaparib, Krebs-2 carcinoma, Lewis carcinoma

References

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