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Tytuł pozycji:

3,6-Disubstituted 1,2,4-Triazolo[3,4-b]Thiadiazoles with Anticancer Activity Targeting Topoisomerase II Alpha

Tytuł:
3,6-Disubstituted 1,2,4-Triazolo[3,4-b]Thiadiazoles with Anticancer Activity Targeting Topoisomerase II Alpha
Autorzy:
Sagredou S
Dalezis P
Nikoleousakos N
Nikolaou M
Voura M
Almpanakis K
Panayiotidis MI
Sarli V
Trafalis DT
Temat:
triazoles
thiadiazoles
topoisomerase iiα
catalytic cycle
ser-1106
phosphorylation
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Źródło:
OncoTargets and Therapy, Vol Volume 13, Pp 7369-7386 (2020)
Wydawca:
Dove Medical Press, 2020.
Rok publikacji:
2020
Kolekcja:
LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Typ dokumentu:
article
Opis pliku:
electronic resource
Język:
English
ISSN:
1178-6930
Relacje:
https://www.dovepress.com/36-disubstituted-124-triazolo34-bthiadiazoles-with-anticancer-activity-peer-reviewed-article-OTT; https://doaj.org/toc/1178-6930
Dostęp URL:
https://doaj.org/article/44b270aa83bd4ee6b9efc07cbec69b66  Link otwiera się w nowym oknie
Numer akcesji:
edsdoj.44b270aa83bd4ee6b9efc07cbec69b66
Czasopismo naukowe
Sofia Sagredou,1 Panagiotis Dalezis,1 Nikolaos Nikoleousakos,1 Michail Nikolaou,1 Maria Voura,2 Konstantinos Almpanakis,2 Mihalis I Panayiotidis,3,4 Vasiliki Sarli,2 Dimitrios T Trafalis1 1Laboratory of Pharmacology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece; 2Department of Chemistry, Aristotle University of Thessaloniki , Thessaloniki, 54124, Greece; 3Department of Electron Microscopy & Molecular Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; 4The Cyprus School of Molecular Medicine, Nicosia 1683, CyprusCorrespondence: Sofia Sagredou; Dimitrios T Trafalis Email ssagredou@med.uoa.gr; dtrafal@med.uoa.grBackground: Topoisomerase IIα (topIIα) maintains the topology of DNA in order to ensure the proper functioning of numerous DNA processes. Inhibition of topIIα leads to the killing of cancer cells thus constituting such inhibitors as useful tools in cancer therapeutics. Triazolo[3,4-b]thiadiazole derivatives are known for their wide range of pharmacological activities while previous studies have documented their in vitro anticancer activity. The purpose of the current study was to investigate if these chemical compounds can act as topIIα inhibitors in cell-free and cell-based systems.Materials and Methods: The MTT assay was performed in DLD-1, HT-29, and LoVo cancer cells so as to evaluate the antiproliferative activity of KA25, KA26, and KA39 triazolo[3,4-b]thiadiazole derivatives. The KA39 compound was tested as a potential topIIα inhibitor using the plasmid-based topoisomerase II drug screening kit. The inhibitory effect of the three derivatives on topIIα phosphorylation was studied in HT-29 and LoVo cancer cells according to Human Phospho-TOP2A/Topoisomerase II Alpha Cell-Based Phosphorylation ELISA Kit. Moreover, flow cytometry was utilized in order to explore apoptotic induction and cell cycle growth arrest, upon treatment with KA39, in DLD-1 and HT-29 cells, respectively. In silico studies were also carried out for further investigation.Results: All three triazolo[3,4-b]thiadiazole derivatives showed an in vitro antiproliferative effect with the KA39 compound being the most potent one. Our results indicated that KA39 induced both early and late apoptosis as well as cell cycle growth arrest in S phase. In addition, the compound blocked the relaxation of supercoiled DNA while it also inhibited topIIα phosphorylation (upon treatment; P< 0.001).Conclusion: Among the three triazolo[3,4-b]thiadiazole derivatives, KA39 was shown to be the most potent anticancer agent and catalytic inhibitor of topIIα phosphorylation as well.Keywords: triazoles, thiadiazoles, topoisomerase IIα, catalytic cycle, Ser-1106, phosphorylation
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