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NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells
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dc.contributor.author | Shahid, Muhammed Akbar | |
dc.contributor.author | Um, In Hwa | |
dc.contributor.author | Elshani, Mustafa | |
dc.contributor.author | Zhang, Ying | |
dc.contributor.author | Harrison, David James | |
dc.date.accessioned | 2022-12-16T17:30:04Z | |
dc.date.available | 2022-12-16T17:30:04Z | |
dc.date.issued | 2022-12-15 | |
dc.identifier | 282587685 | |
dc.identifier | 7634e326-42ec-41e3-982b-6357abc7a286 | |
dc.identifier | 85144169789 | |
dc.identifier | 000925175100043 | |
dc.identifier.citation | Shahid , M A , Um , I H , Elshani , M , Zhang , Y & Harrison , D J 2022 , ' NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells ' , PLoS ONE , vol. 17 , no. 12 , e0278209 . https://doi.org/10.1371/journal.pone.0278209 | en |
dc.identifier.issn | 1932-6203 | |
dc.identifier.other | ORCID: /0000-0001-9041-9988/work/124889149 | |
dc.identifier.other | ORCID: /0000-0001-9999-4292/work/158122916 | |
dc.identifier.uri | https://hdl.handle.net/10023/26617 | |
dc.description | Funding: This study was supported by research funding from NuCana plc to all authors. | en |
dc.description.abstract | Acute myeloid leukemia (AML) stem cells are required for the initiation and maintenance of the disease. Activation of the Wnt/β-catenin pathway is required for the survival and development of AML leukaemia stem cells (LSCs) and therefore, targeting β-catenin is a potential therapeutic strategy. NUC-7738, a phosphoramidate transformation of 3’-deoxyadenosine (3’-dA) monophosphate, is specifically designed to generate the active anti-cancer metabolite 3’-deoxyadenosine triphosphate (3’-dATP) intracellularly, bypassing key limitations of breakdown, transport, and activation. NUC-7738 is currently in a Phase I/II clinical study for the treatment of patients with advanced solid tumors. Protein expression and immunophenotypic profiling revealed that NUC-7738 caused apoptosis in AML cell lines through reducing PI3K-p110α, phosphorylated Akt (Ser473) and phosphorylated GSK3β (Ser9) resulting in reduced β-catenin, c-Myc and CD44 expression. NUC-7738 reduced β-catenin nuclear expression in AML cells. NUC-7738 also decreased the percentage of CD34+ CD38- CD123+ (LSC-like cells) from 81% to 47% and reduced the total number and size of leukemic colonies. These results indicate that therapeutic targeting of the PI3K/Akt/GSK3β axis can inhibit β-catenin signalling, resulting in reduced clonogenicity and eventual apoptosis of AML cells. | |
dc.format.extent | 13 | |
dc.format.extent | 43587 | |
dc.format.extent | 1922343 | |
dc.language.iso | eng | |
dc.relation.ispartof | PLoS ONE | en |
dc.subject | RC0254 Neoplasms. Tumors. Oncology (including Cancer) | en |
dc.subject | NDAS | en |
dc.subject | SDG 3 - Good Health and Well-being | en |
dc.subject | MCC | en |
dc.subject.lcc | RC0254 | en |
dc.title | NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells | en |
dc.type | Journal article | en |
dc.contributor.institution | University of St Andrews. Cellular Medicine Division | en |
dc.contributor.institution | University of St Andrews. School of Medicine | en |
dc.contributor.institution | University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis | en |
dc.identifier.doi | 10.1371/journal.pone.0278209 | |
dc.description.status | Peer reviewed | en |
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