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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

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

  • Tatyana E. Kornienko1
  • Alexandra L. Zakharenko1
  • Irina A. Chernyshova1,2
  • Arina A. Chepanova1,2
  • Nadezhda S. Dyrkheeva1
  • Alina A. Firsova3,4
  • Artem D. Rogachev3,4
  • Olga A. Luzina3
  • Nelly A. Popova2,5
  • Varvara P. Maksimova6
  • Olga A. Vlasova6
  • Valentina P. Deryagina6
3 more authors
  • Alexander Ya. Rodnyy2
  • Nariman F. Salakhutdinov3
  • Olga I. Lavrik1,5,7
7 affiliations
  1. 1Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
  2. 2Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia
  3. 3N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia
  4. 4Institute of Medicine and Medical Technologies, Novosibirsk State University, Pirogov St., 2, 630090 Novosibirsk, Russia
  5. 5Department of Natural Sciences, Novosibirsk State University, Pirogov St., 2, 630090 Novosibirsk, Russia
  6. 6N.N. Blokhin National Medical Research Center of Oncology, 24 Kashirskoe Shosse, 115478 Moscow, Russia
  7. 7The Institute of Biology and Biotechnology, Altai State University, Pr. Lenina 61, 656049 Barnaul, Russia
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{kornienko2026safety,
  title = {{Safety and Antitumor Activity of the Usnic Acid Derivative OL9-116, a TDP1 Inhibitor, as an Adjunctive Therapy in Combination with Topotecan}},
  author = {Tatyana E. Kornienko and Alexandra L. Zakharenko and Irina A. Chernyshova and Arina A. Chepanova and Nadezhda S. Dyrkheeva and Alina A. Firsova and Artem D. Rogachev and Olga A. Luzina and Nelly A. Popova and Varvara P. Maksimova and Olga A. Vlasova and Valentina P. Deryagina and Alexander Ya. Rodnyy and Nariman F. Salakhutdinov and Olga I. Lavrik},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27209266},
  url = {https://www.mdpi.com/1422-0067/27/20/9266},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Safety and Antitumor Activity of the Usnic Acid Derivative OL9-116, a TDP1 Inhibitor, as an Adjunctive Therapy in Combination with Topotecan
AU  - Tatyana E. Kornienko
AU  - Alexandra L. Zakharenko
AU  - Irina A. Chernyshova
AU  - Arina A. Chepanova
AU  - Nadezhda S. Dyrkheeva
AU  - Alina A. Firsova
AU  - Artem D. Rogachev
AU  - Olga A. Luzina
AU  - Nelly A. Popova
AU  - Varvara P. Maksimova
AU  - Olga A. Vlasova
AU  - Valentina P. Deryagina
AU  - Alexander Ya. Rodnyy
AU  - Nariman F. Salakhutdinov
AU  - Olga I. Lavrik
PY  - 2026
DA  - 2026/10/01
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27209266
UR  - https://www.mdpi.com/1422-0067/27/20/9266
AB  - 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.
SN  - 1422-0067
ER  -