Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives
Autor: | Paulo Michel Pinheiro Ferreira, Teresinha Gonçalves da Silva, Marina Galdino da Rocha Pitta, Francisco W.A. Barros, Ivan da Rocha Pitta, Daniel P. Bezerra, Letícia V. Costa-Lotufo, Manoel Odorico de Moraes, João Antonio Pêgas Henriques, Cláudia Pessoa, Temenouga N. Guecheva, Maria do Carmo Alves de Lima, Bruno C. Cavalcanti, Suely Lins Galdino, Rommel Rodríguez Burbano |
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Rok vydání: | 2013 |
Předmět: |
Programmed cell death
Cell Survival Thiazacridine Apoptosis DNA Fragmentation Saccharomyces cerevisiae Toxicology chemistry.chemical_compound Cell Line Tumor DNA topoisomerase I Humans Acridine Thiazolidine Telomerase Caspase Pharmacology biology Apoptose Topoisomerase Acridine orange Molecular biology Biochemistry chemistry DNA Topoisomerases Type I Microscopy Fluorescence Caspases Colonic Neoplasms biology.protein DNA fragmentation Acridines Thiazolidinediones Comet Assay Ethidium bromide DNA Topoisomerases Tipo I DNA |
Zdroj: | Repositório Institucional da Universidade Federal do Ceará (UFC) Universidade Federal do Ceará (UFC) instacron:UFC |
ISSN: | 0041-008X |
DOI: | 10.1016/j.taap.2013.01.010 |
Popis: | Thiazacridine derivatives (ATZD) are a novel class of cytotoxic agents that combine an acridine and thiazolidine nucleus. In this study, the cytotoxic action of four ATZD were tested in human colon carcinoma HCT-8 cells: (5Z)-5-acridin-9-ylmethylene-3-(4-methylbenzyl)-thiazolidine-2,4-dione — AC-4; (5ZE)-5-acridin-9-ylmethylene-3-(4-bromo-benzyl)-thiazolidine-2,4-dione — AC-7; (5Z)-5-(acridin-9-ylmethylene)-3-(4-chloro-benzyl)-1,3-thiazolidine-2,4-dione — AC-10; and (5ZE)-5-(acridin-9-ylmethylene)-3-(4-fluoro-benzyl)-1,3-thiazolidine-2,4-dione — AC-23. All of the ATZD tested reduced the proliferation of HCT-8 cells in a concentration- and time-dependent manner. There were significant increases in internucleosomal DNA fragmentation without affecting membrane integrity. For morphological analyses, hematoxylin–eosin and acridine orange/ethidium bromide were used to stain HCT-8 cells treated with ATZD, which presented the typical hallmarks of apoptosis. ATZD also induced mitochondrial depolarisation and phosphatidylserine exposure and increased the activation of caspases 3/7 in HCT-8 cells, suggesting that this apoptotic cell death was caspase-dependent. In an assay using Saccharomyces cerevisiae mutants with defects in DNA topoisomerases 1 and 3, the ATZD showed enhanced activity, suggesting an interaction between ATZD and DNA topoisomerase enzyme activity. In addition, ATZD inhibited DNA topoisomerase I action in a cell-free system. Interestingly, these ATZD did not cause genotoxicity or inhibit the telomerase activity in human lymphocyte cultures at the experimental levels tested. In conclusion, the ATZD inhibited the DNA topoisomerase I activity and induced tumour cell death through apoptotic pathways. |
Databáze: | OpenAIRE |
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