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


ABSTRACT: Background:Topoisomerase II? (topII?) maintains the topology of DNA in order to ensure the proper functioning of numerous DNA processes. Inhibition of topII? 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 topII? 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 topII? inhibitor using the plasmid-based topoisomerase II drug screening kit. The inhibitory effect of the three derivatives on topII? 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 topII? 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 topII? phosphorylation as well.

SUBMITTER: Sagredou S 

PROVIDER: S-EPMC7395825 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Sagredou Sofia S   Dalezis Panagiotis P   Nikoleousakos Nikolaos N   Nikolaou Michail M   Voura Maria M   Almpanakis Konstantinos K   Panayiotidis Mihalis I MI   Sarli Vasiliki V   Trafalis Dimitrios T DT  

OncoTargets and therapy 20200728


<h4>Background</h4>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-<i>b</i>]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 i  ...[more]

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