The Influence of TDP1 Inhibitor Usnic Acid Derivative OL9-116 on the Effects of Topotecan in Human Cells

Le résumé fourni par la source

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a key enzyme for the repair of stalled topoisomerase 1 (TOP1)-DNA complexes. We previously developed a TDP1 inhibitor, compound OL9-116, which is capable of enhancing the action of the anticancer drug topotecan (TPC), a TOP1 poison, in vitro and in vivo. In this study, the inhibition mode of OL9-116 (uncompetitive) was investigated. N-terminal domain of TDP1, which is important for the cell function of TDP1 but is not involved in catalysis directly, reduces the inhibitory potency of OL9-116 probably by influencing the conformation of the enzyme. OL9-116 does not reduce cell viability and does not affect mitochondrial membrane potential. OL9-116 enhances the cytotoxic/antiproliferative effect of TPC on the panel of tumor cells. This effect is not observed on nontumor cells or TDP1-deficient cells. OL9-116 and TPC have different effects on TDP1 and TOP1 gene expression detected by PCR depending on the cell type and the presence of functional TDP1, but the direct relation between the effects of the compounds on the gene expression and cell survival was not found. The obtained data indicate a synergistic effect of OL9-116 and TPC, which appears to be mediated by TDP1 inhibition rather than by an effect on TDP1 gene expression.

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