Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives

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-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.

Human topoisomerase inhibition and DNA/BSA binding of Ru(II)–SCAR complexes as potential anticancer candidates for oral application

“…Considering that tumor cells often show increased amounts of Top 1, these cells should be more sensitive to the effects of enzyme inhibitors (Barros et al 2013). This fact may support the cytotoxic and selective effects of SCAR 4 and 5.…”

“…Low IC 50 values and potent Top 1 inhibition show that SCAR 5 is a promising candidate for anticancer therapy. The high cytotoxicity in tumor cells, mainly derived from prostate and breast carcinomas can be explained by a largely high activity of Top 1 inhibition, causing the blockage of Top 1 cleavage complex or the inhibition of catalytic activity of Top 1 (Barros et al 2013). The inhibition of Top 1 undermines the enzyme's capacity to regulate the number of topological connections of the DNA strands (Roca 1995).…”

“…Most anticancer agents are designed to act in cell proliferation, inhibiting DNA replication. Human DNA topoisomerase IB (Top 1) is primarily an essential enzyme that aids in solving topological problems associated with DNA replication and transcription (Roca 1995), and often overexpressed in cancerous cells (Barros et al 2013). Oddly enough, while numerous reports have demonstrated the potential of ruthenium(II) complexes focusing on DNA interaction (Barton et al 2011), albumin interaction (Nišavić et al 2016) and cytotoxicity (Gou et al 2015), their ability when it comes to the simultaneous inhibition of Top 1 activity has, nonetheless, been given very little attention.…”

Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives

“…In the fight against cancer, search for new chemical entities (NCEs) with chemotherapeutic properties is really worthy and numerous methods have been utilized to acquire compounds, including isolation from plants and animals and the use of synthetic and combinatorial chemistry and molecular modeling [19,[28][29][30][31].…”

Evaluation of cytotoxic and antitumor activity of perillaldehyde 1,2-epoxide

“…The analysis of cell viability in HL-60 leukemic cell lines was performed by trypan blue exclusion after 72 h of exposure. Trypan blue exclusion test allows separately quantify the viable cells of cells killed by the test compound (Barros et al, 2013). Perilladehyde 1,2epoxide caused a significant reduction in the number of viable cells (p < 0.05) and increase in the number of nonviable cells (p < 0.05) at the concentrations of 4.…”