Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin.
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 scree...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2021
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| Online Access: | http://purl.org/au-research/grants/nhmrc/1059804 http://hdl.handle.net/20.500.11937/83366 |
| _version_ | 1848764577254211584 |
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| author | Karsa, Mawar Kosciolek, Angelika Bongers, Angelika Mariana, Anna Failes, Tim Gifford, Andrew J Kees, Ursula R Cheung, Laurence Kotecha, Rishi Arndt, Greg M Haber, Michelle Norris, Murray D Sutton, Rosemary Lock, Richard B Henderson, Michelle J Somers, Klaartje |
| author_facet | Karsa, Mawar Kosciolek, Angelika Bongers, Angelika Mariana, Anna Failes, Tim Gifford, Andrew J Kees, Ursula R Cheung, Laurence Kotecha, Rishi Arndt, Greg M Haber, Michelle Norris, Murray D Sutton, Rosemary Lock, Richard B Henderson, Michelle J Somers, Klaartje |
| author_sort | Karsa, Mawar |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T11:21:34Z |
| format | Journal Article |
| id | curtin-20.500.11937-83366 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | eng |
| last_indexed | 2025-11-14T11:21:34Z |
| publishDate | 2021 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-833662021-08-15T23:38:15Z Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin. Karsa, Mawar Kosciolek, Angelika Bongers, Angelika Mariana, Anna Failes, Tim Gifford, Andrew J Kees, Ursula R Cheung, Laurence Kotecha, Rishi Arndt, Greg M Haber, Michelle Norris, Murray D Sutton, Rosemary Lock, Richard B Henderson, Michelle J Somers, Klaartje 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. 2021 Journal Article http://hdl.handle.net/20.500.11937/83366 10.1038/s41416-021-01332-x eng http://purl.org/au-research/grants/nhmrc/1059804 http://purl.org/au-research/grants/nhmrc/1157871 restricted |
| spellingShingle | Karsa, Mawar Kosciolek, Angelika Bongers, Angelika Mariana, Anna Failes, Tim Gifford, Andrew J Kees, Ursula R Cheung, Laurence Kotecha, Rishi Arndt, Greg M Haber, Michelle Norris, Murray D Sutton, Rosemary Lock, Richard B Henderson, Michelle J Somers, Klaartje Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin. |
| title | Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin. |
| title_full | Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin. |
| title_fullStr | Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin. |
| title_full_unstemmed | Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin. |
| title_short | Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin. |
| title_sort | exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin. |
| url | http://purl.org/au-research/grants/nhmrc/1059804 http://purl.org/au-research/grants/nhmrc/1059804 http://hdl.handle.net/20.500.11937/83366 |