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dc.contributor.authorThomas, A.*
dc.contributor.authorPerry, T.*
dc.contributor.authorBerhane, S.*
dc.contributor.authorOldreive, C.*
dc.contributor.authorZlatanou, A.*
dc.contributor.authorWilliams, L.R.*
dc.contributor.authorWeston, V.J.*
dc.contributor.authorStankovic, T.*
dc.contributor.authorKearns, P.*
dc.contributor.authorPors, Klaus*
dc.contributor.authorGrand, R.J.*
dc.contributor.authorStewart, G.S.*
dc.date.accessioned2016-09-21T17:19:34Z
dc.date.available2016-09-21T17:19:34Z
dc.date.issued01/06/2015
dc.identifier.citationThomas A, Perry T, Berhane S et al (2015) The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53. Oncogene. 34(25): 3336-3348.
dc.identifier.urihttp://hdl.handle.net/10454/9412
dc.descriptionYes
dc.description.abstractTopoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes.
dc.language.isoen
dc.rights© 2015 The Authors. Full-text reproduced in accordance with the publisher's self-archiving policy.
dc.subjectAnimals
dc.subjectAnthraquinones
dc.subjectAntigens
dc.subjectAntineoplastic agents
dc.subjectAtaxia telangiectasia mutated proteins
dc.subjectCell death
dc.subjectCell line
dc.subjectDNA damage
dc.subjectDNA repair
dc.subjectDNA replication
dc.subjectDNA topoisomerases
dc.subjectDNA-Binding proteins
dc.subjectDose-response relationship
dc.subjectG2 phase cell cycle checkpoints
dc.subjectHumans
dc.subjectLeukemia
dc.subjectM phase cell cycle checkpoints
dc.subjectMice
dc.subjectTopoisomerase inhibitors
dc.subjectTumor suppressor protein p53
dc.subjectXenograft model antitumor assays
dc.titleThe dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53
dc.status.refereedYes
dc.typeArticle
dc.type.versionAccepted manuscript
dc.identifier.doihttps://doi.org/10.1038/onc.2014.266
dc.rights.licenseUnspecified
refterms.dateFOA2018-07-25T14:27:47Z
dc.openaccess.statusopenAccess


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