TY - JOUR

T1 - Antitumor Activity of the Combination of Topotecan and Tyrosyl-DNA-Phosphodiesterase 1 Inhibitor on Model Krebs-2 Mouse Ascite Carcinoma

AU - Dyrkheeva, N. S.

AU - Zakharenko, A. L.

AU - Novoselova, E. S.

AU - Chepanova, A. A.

AU - Popova, N. A.

AU - Nikolin, V. P.

AU - Luzina, O. A.

AU - Salakhutdinov, N. F.

AU - Ryabchikova, E. I.

AU - Lavrik, O. I.

N1 - Funding Information: This work was carried out with the financial support of the Russian Foundation for Basic Research (grant no. 17-00-00097 COMFI) and the Russian State funded project (no. 0245-2021-0009). Publisher Copyright: © 2021, Pleiades Publishing, Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/3

Y1 - 2021/3

N2 - Topotecan is a cytostatic drug from the camptothecin group, it acts by inhibiting topoisomerase 1 (TOP1). Tyrosyl-DNA phosphodiesterase 1 (TDP1) is capable of interfering with the action of TOP1 inhibitors, reducing their therapeutic efficacy. Suppression of TDP1 activity may enhance the effects of topotecan. In this work, we investigated the effect of the antitumor drug topotecan alone and in combination with a TDP1 inhibitor, a hydrazinothiazole derivative of usnic acid, on Krebs-2 mouse ascites tumors. We have previously shown that this derivative efficiently inhibits TDP1. In the present work, we show that both topotecan and the TDP1 inhibitor have an antitumor effect when evaluated separately. The combination of topotecan and the TDP1 inhibitor additively reduces both the weight of the ascites tumor and the number of cells in ascites. In mice, the TDP1 inhibitor alone or in combination with topotecan eliminated the tumor cells. After the combined intraperitoneal administration of these two compounds, we observed cells in which lipid droplets occupied almost the entire cytoplasm and the accumulation of cell detritus, which was absent in the samples collected from mice treated with each compound separately.

AB - Topotecan is a cytostatic drug from the camptothecin group, it acts by inhibiting topoisomerase 1 (TOP1). Tyrosyl-DNA phosphodiesterase 1 (TDP1) is capable of interfering with the action of TOP1 inhibitors, reducing their therapeutic efficacy. Suppression of TDP1 activity may enhance the effects of topotecan. In this work, we investigated the effect of the antitumor drug topotecan alone and in combination with a TDP1 inhibitor, a hydrazinothiazole derivative of usnic acid, on Krebs-2 mouse ascites tumors. We have previously shown that this derivative efficiently inhibits TDP1. In the present work, we show that both topotecan and the TDP1 inhibitor have an antitumor effect when evaluated separately. The combination of topotecan and the TDP1 inhibitor additively reduces both the weight of the ascites tumor and the number of cells in ascites. In mice, the TDP1 inhibitor alone or in combination with topotecan eliminated the tumor cells. After the combined intraperitoneal administration of these two compounds, we observed cells in which lipid droplets occupied almost the entire cytoplasm and the accumulation of cell detritus, which was absent in the samples collected from mice treated with each compound separately.

KW - Krebs-2 carcinoma

KW - Tdp1 inhibitor

KW - topoisomerase 1

KW - topotecan

KW - tyrosyl-DNA phosphodiesterase 1

UR - http://www.scopus.com/inward/record.url?scp=85105086411&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/96477d0c-e38c-3396-9ef7-f9f9ee3f25d1/

U2 - 10.1134/S0026893321020060

DO - 10.1134/S0026893321020060

M3 - Article

AN - SCOPUS:85105086411

VL - 55

SP - 273

EP - 277

JO - Molecular Biology

JF - Molecular Biology

SN - 0026-8933

IS - 2

ER -