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Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells

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Summary

A panel of novel ellipticine isomers were designed and synthesised with the aim of evaluating their anti-cancer effects on selected leukaemia cell lines. A preliminary NCI 60-cell screen demonstrated that these compounds display promising anti-tumour activity across a number of different cell types. We have consequently examined the effect of these derivatives in detail on the Acute Myeloid Leukaemia (AML) cell line, MV4-11. Cell cycle analyses revealed that the compounds had a range of distinctive cell cycle effects. 7-Hydroxyisoellipticine showed the most promise with respect to cytostatic activity. We demonstrated that this compound inhibited proliferation of leukaemia cells by preventing cells from progressing from G2 phase into mitosis over a period of 24 h at a concentration of 5 μM. Our research suggests that this is mediated by an induction of reactive oxygen species (ROS), which in turn activates the DNA damage response pathway. As a result of the activation of p53, cyclin B1 is inhibited. The induction of this pathway leads to apoptosis which is seen at 48 h using the same dose of 7-hydroxyisoellipticine. This study provides for the first time detailed cellular information on the potential use of isoellipticines as chemotherapeutic agents.

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Acknowledgments

This work was supported by the Programme for Research in Third-Level Institutions (PRTLI), the Irish Cancer Society and the Children’s Leukaemia Research Project and the Irish Research Council by means of an IRCSET scholarship award.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. School of Biochemistry and Cell Biology, University College Cork, College Road, Cork, Ireland

    E. G. Russell, J. Stanicka & T. G. Cotter

  2. Department of Chemistry and ABCRF, University College Cork, College Road, Cork, Ireland

    E. C. O’Sullivan, C. M. Miller & F. O. McCarthy

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  1. E. G. Russell
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  2. E. C. O’Sullivan
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  3. C. M. Miller
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Correspondence to T. G. Cotter.

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Russell, E.G., O’Sullivan, E.C., Miller, C.M. et al. Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells. Invest New Drugs 32, 1113–1122 (2014). https://doi.org/10.1007/s10637-014-0140-3

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  • DOI: https://doi.org/10.1007/s10637-014-0140-3

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