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dc.contributor.authorMétayer, Lucy Een
dc.contributor.authorBrown, Richard Den
dc.contributor.authorCarlebur, Saskiaen
dc.contributor.authorBurke, GA Amosen
dc.contributor.authorBrown, Guyen
dc.date.accessioned2019-01-08T00:31:30Z
dc.date.available2019-01-08T00:31:30Z
dc.date.issued2019-02en
dc.identifier.issn1360-8185
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287624
dc.description.abstractArginase has therapeutic potential as a cytotoxic agent in some cancers, but this is unclear for precursor B acute lymphoblastic leukaemia (pre-B ALL), the commonest form of childhood leukaemia. We compared arginase cytotoxicity with asparaginase, currently used in pre-B ALL treatment, and characterised the forms of cell death induced in a pre-B ALL cell line 697. Arginase and asparaginase both efficiently killed 697 cells and mature B lymphoma cell line Ramos, but neither enzyme killed normal lymphocytes. Arginase depleted cellular arginine, and arginase-treated media induced cell death, blocked by addition of arginine or arginine-precursor citrulline. Asparaginase depleted both asparagine and glutamine, and asparaginase-treated media induced cell death, blocked by asparagine, but not glutamine. Both enzymes induced caspase cleavage and activation, chromatin condensation and phosphatidylserine exposure, indicating apoptosis. Both arginase- and asparaginase-induced death were blocked by caspase inhibitors, but with different sensitivities. BCL-2 overexpression inhibited arginase- and asparaginase-induced cell death, but did not prevent arginase-induced cytostasis, indicating a different mechanism of growth arrest. An autophagy inhibitor, chloroquine, had no effect on the cell death induced by arginase, but doubled the cell death induced by asparaginase. In conclusion, arginase causes death of lymphoblasts by arginine-depletion induced apoptosis, via mechanism distinct from asparaginase. Therapeutic implications for childhood ALL include: arginase might be used as treatment (but antagonised by dietary arginine and citrulline), chloroquine may enhance efficacy of asparaginase treatment, and partial resistance to arginase and asparaginase may develop by BCL-2 expression. Arginase or asparaginase might potentially be used to treat Burkitt lymphoma.
dc.format.mediumPrinten
dc.languageengen
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCell Line, Tumoren
dc.subjectHumansen
dc.subjectAsparaginaseen
dc.subjectArginaseen
dc.subjectAntineoplastic Agentsen
dc.subjectCell Deathen
dc.subjectApoptosisen
dc.subjectChilden
dc.subjectPrecursor Cell Lymphoblastic Leukemia-Lymphomaen
dc.subjectPrecursor Cells, B-Lymphoiden
dc.titleMechanisms of cell death induced by arginase and asparaginase in precursor B-cell lymphoblasts.en
dc.typeArticle
prism.endingPage156
prism.issueIdentifier1-2en
prism.publicationDate2019en
prism.publicationNameApoptosis : an international journal on programmed cell deathen
prism.startingPage145
prism.volume24en
dc.identifier.doi10.17863/CAM.34936
dcterms.dateAccepted2018-12-06en
rioxxterms.versionofrecord10.1007/s10495-018-1506-3en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-02en
dc.contributor.orcidBrown, Guy [0000-0002-3610-1730]
dc.identifier.eissn1573-675X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idLeukaemia & Lymphoma Research (10027)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International