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Inhibition of topoisomerase II α activity and induction of apoptosis in mammalian cells by semi-synthetic andrographolide analogues

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Summary

Topoisomerase II α enzyme plays a critical role in DNA replication process. It controls the topologic states of DNA during transcription and is essential for cell proliferation. Human DNA topoisomerase II α (hTopo II α) is a promising chemotherapeutic target for anticancer agents against a variety of cancer types. In the present study, andrographolide and its structurally modified analogues were investigated for their inhibitory activities on hTopo II α enzyme. Five out of nine andrographolide analogues potently reduced hTopo II α activity and inhibited cell proliferation in four mammalian cell lines (Hela, CHO, BCA-1 and HepG2 cells). IC50 values for cytotoxicity of analogues 3A.1, 3A.2, 3A.3, 1B and 2C were 4 to 7 μM. Structure-activity relationship studies revealed that both core structure of andrographolide and silicon based molecule of functional group were important for the inhibition of hTopo II α activity whereas position C-19 of analogues was required for anti-proliferation. In addition, the analogue 2C at 10 μM concentration inhibited hTopo II α, and induced apoptosis with nuclear fragmentation and formation of apoptotic bodies in HepG2 cells. The analogue 2C may, therefore, have a therapeutic potential as effective anticancer agent targeting the hTopo II α functions.

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Acknowledgements

This research project is supported by Mahidol University, the Center of Excellence on Environmental Health, Toxicology, Science & Technology Postgraduate Education and Research Development Office (PERDO), Ministry of Education, Thailand, and the Office of the Higher Education Commission and Mahidol University under the National Research universities (NRU). We are grateful to Prof. Chumpol Pholpramool for his critical reading on the manuscript.

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Authors and Affiliations

  1. Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand

    Jintapat Nateewattana & Pawinee Piyachaturawat

  2. Department of Chemistry, Faculty of Science, Burapha University, Chonburi, 20131, Thailand

    Rungnapha Saeeng & Sakkasem Kasemsook

  3. Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand

    Kanoknetr Suksen, Suman Dutta, Surawat Jariyawat, Arthit Chairoungdua & Pawinee Piyachaturawat

  4. Department of Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, 10240, Thailand

    Apichart Suksamrarn

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  1. Jintapat Nateewattana
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Correspondence to Pawinee Piyachaturawat.

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Nateewattana, J., Saeeng, R., Kasemsook, S. et al. Inhibition of topoisomerase II α activity and induction of apoptosis in mammalian cells by semi-synthetic andrographolide analogues. Invest New Drugs 31, 320–332 (2013). https://doi.org/10.1007/s10637-012-9868-9

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  • DOI: https://doi.org/10.1007/s10637-012-9868-9

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