Abstract
Acridine derivatives are capable of interacting with double-stranded DNA. Some essential enzymes such as DNA topoisomerase I, II and telomerase are the biological targets of these compounds in cancer chemotherapy. 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine is a novel synthetic acridine derivative with antibacterial properties. Selective induction of apoptosis in tumor cells is the characteristic of some clinically effective anticancer drugs. In this study, the cytotoxicity and apoptosis inducing effects of 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine on 5637 cancerous and HFF3 (human foreskin fibroblast) normal cells were investigated for the first time. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay showed that the cytotoxic effects of 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine were more pronounced on 5637 cells in comparison to HFF3 normal cells. 4′,6-diamidino-2-phenylindole staining of 5637 cells demonstrated the presence of condensed chromatin in majority of cells (60 %) which is indicative of apoptosis induction. Besides the results of comet assay revealed that 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine treatment resulted in 10 folds greater DNA damage in cancerous cells (62 %) as compared to normal cells (6 %). Flow cytometry analysis of 5637 cells after propidium iodide staining revealed that 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine causes apoptosis by cell cycle arrest in sub-G1 peak in a time-dependent manner. Moreover, evaluation of caspase 3 activity showed that this compound significantly increased caspase 3 activity in 5637 cells as compared with control cells. Therefore, it can be concluded that 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine has selective cytotoxic and anticancer effects on 5637 cells and a high potential to induce apoptosis. This caspase-dependent apoptotic induction was resulted from DNA damage, which may arise from inhibition of DNA topoisomerase I and/or II activity. Although further studies are required to determine its mechanism in vivo, 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine can be introduced as a potential anticancer compound for further investigations.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have