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7-formyl-10-methylisoellipticine, a novel ellipticine derivative, induces mitochondrial reactive oxygen species (ROS) and shows anti-leukaemic activity in mice

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Summary

Acute myeloid leukaemia (AML) is the most common type of leukaemia in adults and is associated with high relapse rates. Current treatment options have made significant progress but the 5 year survival for AML remains low and therefore, there is an urgent need to develop novel therapeutics. Ellipticines, a class of cancer chemotherapeutic agents, have had limited success clinically due to low solubility and toxic side effects. Isoellipticines, novel isomers of ellipticine, have been designed to overcome these limitations. One particular isoellipticine, 7-formyl-10-methylisoellipticine, has previously showed strong ability to inhibit the growth of leukaemia cell lines. In this study the anti-leukaemia effect of this compound was investigated in detail on an AML cell line, MV4-11. Over a period of 24 h 7-formyl-10-methyl isoellipticine at a concentration of 5 μM can kill up to 40 % of MV4-11 cells. Our research suggests that the cytotoxicity of 7-formyl-10-methylisoellipticine is partially mediated by an induction of mitochondrial reactive oxygen species (ROS). Furthermore, 7-formyl-10-methylisoellipticine demonstrated promising anti-tumour activity in an AML xenograft mouse model without causing toxicity, implying the potential of isoellipticines as novel chemotherapeutic agents in the treatment of leukaemia.

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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, the Irish Research Council by means of an IRCSET scholarship award and the Government of Ireland Postdoctoral Fellowship from Irish Research Council (GOIPD/2013/150).

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Authors and Affiliations

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

    Eileen G. Russell

  2. Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland

    Jianfeng Guo & Caitriona M. O’Driscoll

  3. Department of Chemistry and ABCRF, University College Cork, Cork, Ireland

    Elaine C. O’Sullivan & Florence O. McCarthy

  4. School of Biochemistry & Cell Biology, University College Cork, Cork, Ireland

    Thomas G. Cotter

Authors
  1. Eileen G. Russell
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  2. Jianfeng Guo
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  3. Elaine C. O’Sullivan
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  4. Caitriona M. O’Driscoll
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  5. Florence O. McCarthy
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  6. Thomas G. Cotter
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Corresponding author

Correspondence to Thomas G. Cotter.

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Ethical statement

All animal experimental procedures were approved by the ethical committee at the University College Cork and performed in accordance with the European Union (Protection of Animals Used for Scientific Purposes) Regulations 2012 (S.I. No. 543 of 2012) and Directive 2010/63/EU for animals used for scientific purposes.

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The authors declare that they have no conflict of interest.

Additional information

Eileen G. Russell and Jianfeng Guo shared first authorship.

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Supplementary Fig. 1

PEG solvent mixture has similar toxicity profile to DMSO in vitro. The effects of a range of doses of 7-formyl-10-methylisoellipticine dissolved in either 100 % DMSO or a solution of 30 % polyethylene glycol, 70 % H2O and <1 % DMSO on MV4-11 cells treated for 24 h. Toxicity was measured by propidium iodide staining. The error bars represent ± SD. n = 9 (PPTX 44 kb)

Supplementary Fig. 2

7-Formyl-10-methylisoellipticine does not show signs of toxicity in the organs of BALB/c mice. The lung, spleen, brain, heart, liver and kidney BALB/c mice treated with the control or the indicated does of 7-formyl-10-methylisoellipticine to observe cell morphology and tissue structure (x40) (PPTX 74350 kb)

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Russell, E.G., Guo, J., O’Sullivan, E.C. et al. 7-formyl-10-methylisoellipticine, a novel ellipticine derivative, induces mitochondrial reactive oxygen species (ROS) and shows anti-leukaemic activity in mice. Invest New Drugs 34, 15–23 (2016). https://doi.org/10.1007/s10637-015-0302-y

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  • DOI: https://doi.org/10.1007/s10637-015-0302-y

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