PAUKOVČEKOVÁ, Silvia, Mária KRCHNIAKOVÁ, Petr CHLAPEK, Jakub NERADIL, Jan ŠKODA and Renata VESELSKÁ. Thiosemicarbazones Can Act Synergistically with Anthracyclines to Downregulate CHEK1 Expression and Induce DNA Damage in Cell Lines Derived from Pediatric Solid Tumors. International Journal of Molecular Sciences. Basel: MDPI, 2022, vol. 23, No 15, p. 1-19. ISSN 1661-6596. Available from: https://dx.doi.org/10.3390/ijms23158549.
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Original name Thiosemicarbazones Can Act Synergistically with Anthracyclines to Downregulate CHEK1 Expression and Induce DNA Damage in Cell Lines Derived from Pediatric Solid Tumors
Authors PAUKOVČEKOVÁ, Silvia, Mária KRCHNIAKOVÁ, Petr CHLAPEK, Jakub NERADIL, Jan ŠKODA and Renata VESELSKÁ.
Edition International Journal of Molecular Sciences, Basel, MDPI, 2022, 1661-6596.
Other information
Original language English
Type of outcome Article in a journal
Country of publisher Switzerland
Confidentiality degree is not subject to a state or trade secret
WWW URL
Organization Přírodovědecká fakulta – Repository – Repository
Doi http://dx.doi.org/10.3390/ijms23158549
UT WoS 000838976900001
Keywords in English thiosemicarbazones; anthracyclines; anthracenedione; pediatric solid tumors; combined anticancer treatment; checkpoint kinase 1; double strand breaks in DNA
Links LX22NPO5102, research and development project. MUNI/A/1325/2021, interní kód Repo. MUNI/A/1522/2020, interní kód Repo. NV17-33104A, research and development project.
Changed by Changed by: RNDr. Daniel Jakubík, učo 139797. Changed: 5/1/2023 04:01.
Abstract
Anticancer therapy by anthracyclines often leads to the development of multidrug resistance (MDR), with subsequent treatment failure. Thiosemicarbazones have been previously suggested as suitable anthracycline partners due to their ability to overcome drug resistance through dual Pgp-dependent cytotoxicity-inducing effects. Here, we focused on combining anthracyclines (doxorubicin, daunorubicin, and mitoxantrone) and two thiosemicarbazones (DpC and Dp44mT) for treating cell types derived from the most frequent pediatric solid tumors. Our results showed synergistic effects for all combinations of treatments in all tested cell types. Nevertheless, further experiments revealed that this synergism was independent of Pgp expression but rather resulted from impaired DNA repair control leading to cell death via mitotic catastrophe. The downregulation of checkpoint kinase 1 (CHEK1) expression by thiosemicarbazones and the ability of both types of agents to induce double-strand breaks in DNA may explain the Pgp-independent synergism between anthracyclines and thiosemicarbazones. Moreover, the concomitant application of these agents was found to be the most efficient approach, achieving the strongest synergistic effect with lower concentrations of these drugs. Overall, our study identified a new mechanism that offers an avenue for combining thiosemicarbazones with anthracyclines to treat tumors regardless the Pgp status.
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Thiosemicarbazones_Can_Act_Synergistically_with_Anthracyclines_to_Downregulate_CHEK1_Expression_and_Induce_DNA_Damage_in_Cell_Lines_Derived_from_Pediatric_Solid_Tumors.pdf Licence Creative Commons  File version 21/12/2022

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Thiosemicarbazones_Can_Act_Synergistically_with_Anthracyclines_to_Downregulate_CHEK1_Expression_and_Induce_DNA_Damage_in_Cell_Lines_Derived_from_Pediatric_Solid_Tumors.pdf
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  • a concrete person Mgr. Lucie Vařechová, uco 106253
  • a concrete person RNDr. Daniel Jakubík, uco 139797
  • a concrete person Mgr. Jolana Surýnková, uco 220973
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