TY - JOUR

T1 - The Lipophilic Purine Nucleoside-Tdp1 Inhibitor-Enhances DNA Damage Induced by Topotecan In Vitro and Potentiates the Antitumor Effect of Topotecan In Vivo

AU - Chernyshova, Irina A

AU - Zakharenko, Aleksandra L

AU - Kurochkin, Nikolay N

AU - Dyrkheeva, Nadezhda S

AU - Kornienko, Tatyana E

AU - Popova, Nelly A

AU - Nikolin, Valeriy P

AU - Ilina, Ekaterina S

AU - Zharkov, Timofey D

AU - Kupryushkin, Maxim S

AU - Oslovsky, Vladimir E

AU - Drenichev, Mikhail S

AU - Lavrik, Olga I

N1 - Funding: This research was funded by a grant from the Ministry of Science and Higher Education Russian Federation (agreement No. 075-15-2020-773).

PY - 2023/1

Y1 - 2023/1

N2 - 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.

AB - 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.

KW - Animals

KW - Mice

KW - Humans

KW - Topotecan/pharmacology

KW - Phosphoric Diester Hydrolases/metabolism

KW - Phosphodiesterase Inhibitors/pharmacology

KW - Purine Nucleosides

KW - Structure-Activity Relationship

KW - Topoisomerase I Inhibitors/pharmacology

KW - Esterases/metabolism

KW - DNA Damage

KW - DNA

KW - DNA Topoisomerases, Type I/metabolism

KW - synergy

KW - Tdp1 inhibitor

KW - lipophilic nucleosides

KW - tyrosyl-DNA phosphodiesterase 1

KW - DNA repair

KW - inhibiting activity

KW - topoisomerase I

KW - topotecan

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85145738635&origin=inward&txGid=50335a98340d9ab3b67d1b18b56663cc

UR - https://www.mendeley.com/catalogue/d3c0f954-4d4d-3c74-b616-1a0f3f6ea7ca/

U2 - 10.3390/molecules28010323

DO - 10.3390/molecules28010323

M3 - Article

C2 - 36615517

VL - 28

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 1

M1 - 323

ER -