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Title in Portuguese: Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives
Author: Barros, Francisco W.A.
Bezerra, Daniel P.
Ferreira, Paulo M.P.
Cavalcanti, Bruno C.
Silva, Teresinha G.
Pitta, Marina G.R.
Lima, Maria do C.A. de
Galdino, Suely L.
Pitta, Ivan da R.
Costa-Lotufo, Letícia V.
Moraes Filho, Manoel Odorico de
Burbano, Rommel R.
Guecheva, Temenouga N.
Henriques, João A.P.
Pessoa, Cláudia
Keywords: Apoptose
DNA Topoisomerases Tipo I
Issue Date: Apr-2013
Publisher: Toxicology and Applied Pharmacology
Citation: BARROS, F. W. A. et al. Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives. Toxicology and Applied Pharmacology, San Diego, Calif., v. 268, n. 1, p. 37-46, abr. 2013.
Abstract: 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-chlorobenzyl)- 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 inducedmitochondrial 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.
metadata.dc.type: Artigo de Periódico
ISSN: 1096-0333 On line
0041-008X Impresso
Appears in Collections:DFIFA - Artigos publicados em revista científica

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