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Translational Therapeutics

Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin

Abstract

Background

The prognosis for high-risk childhood acute leukaemias remains dismal and established treatment protocols often cause long-term side effects in survivors. This study aims to identify more effective and safer therapeutics for these patients.

Methods

A high-throughput phenotypic screen of a library of 3707 approved drugs and pharmacologically active compounds was performed to identify compounds with selective cytotoxicity against leukaemia cells followed by further preclinical evaluation in patient-derived xenograft models.

Results

Auranofin, an FDA-approved agent for the treatment of rheumatoid arthritis, was identified as exerting selective anti-cancer activity against leukaemia cells, including patient-derived xenograft cells from children with high-risk ALL, versus solid tumour and non-cancerous cells. It induced apoptosis in leukaemia cells by increasing reactive oxygen species (ROS) and potentiated the activity of the chemotherapeutic cytarabine against highly aggressive models of infant MLL-rearranged ALL by enhancing DNA damage accumulation. The enhanced sensitivity of leukaemia cells towards auranofin was associated with lower basal levels of the antioxidant glutathione and higher baseline ROS levels compared to solid tumour cells.

Conclusions

Our study highlights auranofin as a well-tolerated drug candidate for high-risk paediatric leukaemias that warrants further preclinical investigation for application in high-risk paediatric and adult acute leukaemias.

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Fig. 1: Screening a library of 3707 approved drugs and pharmacologically active compounds to identify novel candidate drugs for high-risk paediatric leukaemia.
Fig. 2: Auranofin reduces the viability of acute leukaemia cells by inducing apoptosis.
Fig. 3: Auranofin induces apoptosis in acute leukaemia cells by inducing ROS.
Fig. 4: The combination of auranofin and cytarabine induces a leukaemia growth delay in a highly chemo-resistant infant MLL-r ALL PDX.

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Acknowledgements

Patient samples and related clinical information for this study were kindly provided by Sydney Children’s Tumour Bank Network. Children’s Cancer Institute Australia is affiliated with UNSW Sydney and The Sydney Children’s Hospitals Network.

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Authors

Contributions

M.K., A.K., A.B., A.M. and A.J.G. conducted the experiments and analysed the data; U.R.K., L.C.C. and R.S.K. provided guidance and access to the cell lines and patient material used in the study; K.S. and M.J.H. conceived the project and designed the experiments. T.F., G.M.A., M.H., M.D.N., R.S. and R.B.L. provided crucial suggestions and support with study design; M.K. wrote the manuscript under the guidance of K.S. and M.J.H. who critically reviewed the manuscript; All authors reviewed the manuscript.

Corresponding author

Correspondence to Michelle J. Henderson.

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Ethics approval and consent to participate

Animal studies were conducted with approval from the Animal Care and Ethics Committee of the University of New South Wales (Sydney, Australia).

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Not applicable.

Data availability

All data generated or analysed during this study are included in this published article and its Supplementary information files.

Competing interests

The authors declare no competing interests.

Funding information

This research was supported by grants from the Anthony Rothe Memorial Trust, the Cancer Council NSW, the Tenix Foundation, the Kids Cancer Alliance, the ISG Foundation, the National Health and Medical Research Council of Australia (NHMRC Fellowships APP1059804 and APP1157871) to R.B.L. and the Children’s Leukaemia & Cancer Research Foundation (Perth, Western Australia) to U.R.K.

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Karsa, M., Kosciolek, A., Bongers, A. et al. Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin. Br J Cancer 125, 55–64 (2021). https://doi.org/10.1038/s41416-021-01332-x

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