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

T E Kornienko, A L Zakharenko, E S Ilina, A A Chepanova, O D Zakharova, N S Dyrkheeva, N A Popova, V P Nikolin, A S Filimonov, O A Luzina, N F Salakhutdinov, O I Lavrik

Molekuliarnaia biologiia 2023 Mar-Apr

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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.

Citation

T E Kornienko, A L Zakharenko, E S Ilina, A A Chepanova, O D Zakharova, N S Dyrkheeva, N A Popova, V P Nikolin, A S Filimonov, O A Luzina, N F Salakhutdinov, O I Lavrik. Effect of Usnic Acid-Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitor Used as Monotherapy or in Combination with Olaparib on Transplanted Tumors In Vivo]. Molekuliarnaia biologiia. 2023 Mar-Apr;57(2):220-231