The Lipophilic Purine Nucleoside-Tdp1 Inhibitor-Enhances DNA Damage Induced by Topotecan In Vitro and Potentiates the Antitumor Effect of Topotecan In Vivo

• Published in: Molecules (Basel, Switzerland) Vol. 28; no. 1; p. 323
• Main Authors: Chernyshova, Irina A, Zakharenko, Aleksandra L, Kurochkin, Nikolay N, Dyrkheeva, Nadezhda S, Kornienko, Tatyana E, Popova, Nelly A, Nikolin, Valeriy P, Ilina, Ekaterina S, Zharkov, Timofey D, Kupryushkin, Maxim S, Oslovsky, Vladimir E, Drenichev, Mikhail S, Lavrik, Olga I
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31.12.2022; MDPI
• Subjects: Adenosine; Antitumor activity; Cancer; Cancer therapies; Chemical properties; Chemotherapy; Comet assay; Cytotoxicity; Damage detection; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Drug sensitization; Enzymes; Hydrocarbons; inhibiting activity; Lipids; Lipophilic; lipophilic nucleosides; Lipophilicity; Nucleosides; Pharmaceutical research; Phosphodiesterase; Physiological aspects; Side effects; Tdp1 inhibitor; topoisomerase I; Topotecan; Toxicity; tyrosyl-DNA phosphodiesterase 1; Russia; inhibiting activity; synergy; Tdp1 inhibitor; lipophilic nucleosides; tyrosyl-DNA phosphodiesterase 1; DNA repair; topoisomerase I; topotecan
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28010323

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 IC 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.