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

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.