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Cytotoxic and anticancer activities of an acridine derivative; 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine on 5637 cells

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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.

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Acknowledgments

This study was supported by a grant from Ferdowsi University of Mashhad. The authors are grateful to Dr. Fatemeh B. Rassouli, Azadeh Haghighitalab, and Mohammad Nakhaei for their technical assistance.

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Authors and Affiliations

  1. Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran

    Halimeh Hassanzadeh, Ahmad Reza Bahrami & Maryam M. Matin

  2. Cell and Molecular Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran

    Ahmad Reza Bahrami & Maryam M. Matin

  3. Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran

    Hamid Sadeghian

  4. Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran

    Mohammad Rahimizadeh

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  1. Halimeh Hassanzadeh
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  2. Ahmad Reza Bahrami
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  3. Hamid Sadeghian
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  4. Mohammad Rahimizadeh
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  5. Maryam M. Matin
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Correspondence to Maryam M. Matin.

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Hassanzadeh, H., Bahrami, A.R., Sadeghian, H. et al. Cytotoxic and anticancer activities of an acridine derivative; 11-chloro-3-methyl-3H-imidazo[4,5-a]acridine on 5637 cells. Med Chem Res 25, 1852–1860 (2016). https://doi.org/10.1007/s00044-016-1637-4

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  • DOI: https://doi.org/10.1007/s00044-016-1637-4

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