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dc.contributor.authorOo, Zay Yar
dc.contributor.authorProctor, Martina
dc.contributor.authorStevenson, Alexander J
dc.contributor.authorNazareth, Deborah
dc.contributor.authorFernando, Madushan
dc.contributor.authorDaignault, Sheena M
dc.contributor.authorLanagan, Catherine
dc.contributor.authorWalpole, Sebastian
dc.contributor.authorBonazzi, Vanessa
dc.contributor.authorSkalamera, Dubravka
dc.contributor.authorSnell, Cameron
dc.contributor.authorHaass, Nikolas K
dc.contributor.authorLarsen, Jill E
dc.contributor.authorGabrielli, Brian
dc.date.accessioned2019-11-25T04:21:57Z
dc.date.available2019-11-25T04:21:57Z
dc.date.issued2019
dc.identifier.issn1574-7891
dc.identifier.doi10.1002/1878-0261.12497
dc.identifier.urihttp://hdl.handle.net/10072/389244
dc.description.abstractDrugs such as gemcitabine that increase replication stress are effective chemotherapeutics in a range of cancer settings. These drugs effectively block replication and promote DNA damage, triggering a cell cycle checkpoint response through the ATR–CHK1 pathway. Inhibiting this signalling pathway sensitises cells to killing by replication stress-inducing drugs. Here, we investigated the effect of low-level replication stress induced by low concentrations (> 0.2 mm) of the reversible ribonucleotide reductase inhibitor hydroxyurea (HU), which slows S-phase progression but has little effect on cell viability or proliferation. We demonstrate that HU effectively synergises with CHK1, but not ATR inhibition, in > 70% of melanoma and non-small-cell lung cancer cells assessed, resulting in apoptosis and complete loss of proliferative potential in vitro and in vivo. Normal fibroblasts and haemopoietic cells retain viability and proliferative potential following exposure to CHK1 inhibitor plus low doses of HU, but normal cells exposed to CHK1 inhibitor combined with submicromolar concentrations of gemcitabine exhibited complete loss of proliferative potential. The effects of gemcitabine on normal tissue correlate with irreversible ATR–CHK1 pathway activation, whereas low doses of HU reversibly activate CHK1 independently of ATR. The combined use of CHK1 inhibitor and subclinical HU also triggered an inflammatory response involving the recruitment of macrophages in vivo. These data indicate that combining CHK1 inhibitor with subclinical HU is superior to combination with gemcitabine, as it provides equal anticancer efficacy but with reduced normal tissue toxicity. These data suggest a significant proportion of melanoma and lung cancer patients could benefit from treatment with this drug combination.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherWiley Open Access
dc.publisher.placeUnited Kingdom
dc.relation.ispartofpagefrom1503
dc.relation.ispartofpageto1518
dc.relation.ispartofissue7
dc.relation.ispartofjournalMolecular Oncology
dc.relation.ispartofvolume13
dc.subject.fieldofresearchOncology and Carcinogenesis
dc.subject.fieldofresearchcode1112
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsOncology
dc.subject.keywordsCHK1 inhibitor
dc.subject.keywordshydroxyurea
dc.titleCombined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationOo, ZY; Proctor, M; Stevenson, AJ; Nazareth, D; Fernando, M; Daignault, SM; Lanagan, C; Walpole, S; Bonazzi, V; Skalamera, D; Snell, C; Haass, NK; Larsen, JE; Gabrielli, B, Combined use of subclinical hydroxyurea and CHK1 inhibitor effectively controls melanoma and lung cancer progression, with reduced normal tissue toxicity compared to gemcitabine, Molecular Oncology, 2019, 13 (7), pp. 1503-1518
dcterms.dateAccepted2019-04-30
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/
dc.date.updated2019-11-21T04:41:05Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorGabrielli, Brian


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