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dc.contributor.authorKarsa, Mawar
dc.contributor.authorKosciolek, Angelika
dc.contributor.authorBongers, Angelika
dc.contributor.authorMariana, Anna
dc.contributor.authorFailes, Tim
dc.contributor.authorGifford, Andrew J
dc.contributor.authorKees, Ursula R
dc.contributor.authorCheung, Laurence
dc.contributor.authorKotecha, Rishi
dc.contributor.authorArndt, Greg M
dc.contributor.authorHaber, Michelle
dc.contributor.authorNorris, Murray D
dc.contributor.authorSutton, Rosemary
dc.contributor.authorLock, Richard B
dc.contributor.authorHenderson, Michelle J
dc.contributor.authorSomers, Klaartje
dc.identifier.citationKarsa, M. and Kosciolek, A. and Bongers, A. and Mariana, A. and Failes, T. and Gifford, A.J. and Kees, U.R. et al. 2021. Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin. British Journal of Cancer.

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.

dc.titleExploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin.
dc.typeJournal Article
dcterms.source.titleBritish Journal of Cancer
curtin.departmentCurtin Medical School
curtin.departmentSchool of Pharmacy and Biomedical Sciences
curtin.accessStatusFulltext not available
curtin.facultyFaculty of Health Sciences
curtin.contributor.orcidCheung, Laurence [0000-0001-6298-5288]
curtin.contributor.orcidKotecha, Rishi [0000-0003-1836-4075]
curtin.contributor.scopusauthoridCheung, Laurence [56663936300]

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