The Lipophilic Purine Nucleoside—Tdp1 Inhibitor—Enhances DNA Damage Induced by Topotecan In Vitro and Potentiates the Antitumor Effect of Topotecan In Vivo
Irina A. Chernyshova,
Aleksandra L. Zakharenko,
Nikolay N. Kurochkin,
Nadezhda S. Dyrkheeva,
Tatyana E. Kornienko,
Nelly A. Popova,
Valeriy P. Nikolin,
Ekaterina S. Ilina,
Timofey D. Zharkov,
Maxim S. Kupryushkin,
Vladimir E. Oslovsky,
Mikhail S. Drenichev,
Olga I. Lavrik
Affiliations
Irina A. Chernyshova
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Aleksandra L. Zakharenko
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Nikolay N. Kurochkin
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
Nadezhda S. Dyrkheeva
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Tatyana E. Kornienko
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Nelly A. Popova
Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Valeriy P. Nikolin
Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Ekaterina S. Ilina
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Timofey D. Zharkov
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Maxim S. Kupryushkin
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Vladimir E. Oslovsky
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
Mikhail S. Drenichev
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
Olga I. Lavrik
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
The use of cancer chemotherapy sensitizers is a promising approach to induce the effect of clinically used anticancer treatments. One of the interesting targets is Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), a DNA-repair enzyme, that may prevent the action of clinical Topoisomerase 1 (Top1) inhibitors, such as topotecan (Tpc). Tdp1 eliminates covalent Top1-DNA (Top1c) complexes that appear under the action of topotecan and determines the cytotoxic effect of this drug. We hypothesize that Tdp1 inhibition would sensitize cells towards the effect of Tpc. Herein, we report the synthesis and study of lipophilic derivatives of purine nucleosides that efficiently suppress Tdp1 activity, with IC50 values in the 0.3–22.0 μM range. We also showed that this compound class can enhance DNA damage induced by topotecan in vitro by Comet assay on human cell lines HeLa and potentiate the antitumor effect of topotecan in vivo on a mice ascitic Krebs-2 carcinoma model. Thereby, this type of compound may be useful to develop drugs, that sensitize the effect of topotecan and reduce the required dose and, as a result, side effects.
