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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.issued2015-06-01
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.descriptionYesen
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.relation.isreferencedbyhttp://dx.doi.org/10.1038/onc.2014.266
dc.rights© 2015 The Authors. Full-text reproduced in accordance with the publisher’s self-archiving policy.en
dc.subjectAnimals
dc.subject; Anthraquinones
dc.subject; Antigens
dc.subject; Antineoplastic agents
dc.subject; Ataxia telangiectasia mutated proteins
dc.subject; Cell death
dc.subject; Cell line
dc.subject; DNA damage
dc.subject; DNA repair
dc.subject; DNA replication
dc.subject; DNA topoisomerases
dc.subject; DNA-Binding proteins
dc.subject; Dose-response relationship
dc.subject; G2 phase cell cycle checkpoints
dc.subject; Humans
dc.subject; Leukemia
dc.subject; M phase cell cycle checkpoints
dc.subject; Mice
dc.subject; Topoisomerase inhibitors
dc.subject; Tumor suppressor protein p53
dc.subject; Xenograft model antitumor assays
dc.titleThe dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53
dc.status.refereedYesen
dc.typeArticle
dc.type.versionAccepted manuscripten
refterms.dateFOA2018-07-25T14:27:47Z


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