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Vol 57(2023) N 2 p. 214-224; DOI 10.1134/S0026893323020127 Full Text

T.E. Kornienko1, A.L. Zakharenko1, E.S. Ilina1,4, A.A. Chepanova1, O.D. Zakharova1, N.S. Dyrkheeva1, N.A. Popova2,4, V.P. Nikolin2, A.S. Filimonov3, O.A. Luzina3, N.F. Salakhutdinov3,4, O.I. Lavrik3,4*

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

1Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia
2Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia
3Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia
4Novosibirsk State University, Novosibirsk, 630090 Russia

*lavrik@niboch.nsc.ru
Received - 2022-07-29; Revised - 2022-08-25; Accepted - 2022-08-25

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.

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



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