Safety and Antitumor Activity of the Usnic Acid Derivative OL9-116, a TDP1 Inhibitor, as an Adjunctive Therapy in Combination with Topotecan

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Topotecan inhibits topoisomerase 1 (TOP1) by trapping the enzyme in a DNA-cleavage complex, which can be repaired by tyrosyl-DNA phosphodiesterase 1 (TDP1). The usnic acid derivative OL9-116 inhibits TDP1 and thereby enhances the antitumor activity of topotecan, making it a promising combination partner. However, the safety and optimal administration schedule of OL9-116 with topotecan have not been characterized. We demonstrated that OL9-116 has no genotoxic or epigenetic effects using Ames and CBMN assays, as well as HeLa trichostatin A-inducible cells with an epigenetically repressed GFP gene. Intraperitoneal administration was found to provide higher bioavailability than intragastric administration. We showed on the RShM-5 cervical cancer model that repeated topotecan administration in a clinically relevant low single-dose regimen was more effective than a single injection, and addition of topotecan at the Tmax of OL9-116 enhanced tumor growth inhibition. In the Lewis lung carcinoma model, the OL9-116–topotecan combination reduced primary tumor mass and lung metastases, enhancing both antitumor and antimetastatic effects. Monitoring of hematological parameters, liver, and spleen indices revealed no clinically significant toxicity. Moreover, peripheral blood parameters improved with the OL9-116–topotecan combination compared with topotecan monotherapy. Collectively, these findings support OL9-116 as a promising safe TDP1 inhibitor for combination with topotecan.