Exploiting the reactive oxygen species imbalance in high-risk paediatric acute lymphoblastic leukaemia through auranofin
Autor: | Richard B. Lock, Michelle J. Henderson, Angelika Bongers, Tim Failes, Mawar Karsa, Anna Mariana, Laurence C. Cheung, Andrew J. Gifford, Angelika Kosciolek, Michelle Haber, Ursula R. Kees, Rosemary Sutton, Greg M. Arndt, Murray D. Norris, Klaartje Somers, Rishi S. Kotecha |
---|---|
Rok vydání: | 2021 |
Předmět: |
Cancer Research
Auranofin Cell Survival DNA damage Phenotypic screening Article Small Molecule Libraries Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Animals Humans Child Cell Proliferation chemistry.chemical_classification Reactive oxygen species business.industry Cytarabine Cancer Drug Synergism Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease Xenograft Model Antitumor Assays High-Throughput Screening Assays Oncology chemistry Apoptosis 030220 oncology & carcinogenesis Rheumatoid arthritis Cancer research Female Drug Screening Assays Antitumor Reactive Oxygen Species business medicine.drug |
Zdroj: | Br J Cancer |
ISSN: | 1532-1827 0007-0920 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |