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dc.contributor.authorUrban-Wójciuk, Z
dc.contributor.authorGraham, A
dc.contributor.authorBarker, K
dc.contributor.authorKwok, C
dc.contributor.authorSbirkov, Y
dc.contributor.authorHowell, L
dc.contributor.authorCampbell, J
dc.contributor.authorWoster, PM
dc.contributor.authorPoon, E
dc.contributor.authorPetrie, K
dc.contributor.authorChesler, L
dc.date.accessioned2021-12-01T09:51:01Z
dc.date.available2021-12-01T09:51:01Z
dc.date.issued2021-09-14
dc.identifier.citationCancer gene therapy, 2021
dc.identifier.issn0929-1903
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4908
dc.identifier.eissn1476-5500
dc.identifier.doi10.1038/s41417-021-00386-6
dc.description.abstractDeregulated polyamine biosynthesis is emerging as a common feature of neuroblastoma and drugs targeting this metabolic pathway such as DFMO are in clinical and preclinical development. The polyamine analog verlindamycin inhibits the polyamine biosynthesis pathway enzymes SMOX and PAOX, as well as the histone demethylase LSD1. Based on our previous research in acute myeloid leukemia (AML), we reasoned verlindamycin may also unblock neuroblastoma differentiation when combined with all-trans-retinoic acid (ATRA). Indeed, co-treatment with verlindamycin and ATRA strongly induced differentiation regardless of MYCN status, but in MYCN-expressing cells, protein levels were strongly diminished. This process was not transcriptionally regulated but was due to increased degradation of MYCN protein, at least in part via ubiquitin-independent, proteasome-dependent destruction. Here we report that verlindamycin effectively induces the expression of functional tumor suppressor-antizyme via ribosomal frameshifting. Consistent with previous results describing the function of antizyme, we found that verlindamycin treatment led to the selective targeting of ornithine decarboxylase (the rate-limiting enzyme for polyamine biosynthesis) as well as key oncoproteins, such as cyclin D and Aurora A kinase. Retinoid-based multimodal differentiation therapy is one of the few interventions that extends relapse-free survival in MYCN-associated high-risk neuroblastoma and these results point toward the potential use of verlindamycin in this regimen.
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleThe biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme.
dc.typeJournal Article
dcterms.dateAccepted2021-08-27
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41417-021-00386-6
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-09-14
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer gene therapy
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics
pubs.publication-statusPublished
pubs.embargo.termsNot known
icr.researchteamPaediatric Solid Tumour Biology and Therapeutics
dc.contributor.icrauthorKwok, Colinen_US
dc.contributor.icrauthorPoon, Evonen_US


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