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The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme.

Urban-Wójciuk, Zuzanna, Graham, Amy, Barker, Karen, Kwok, Colin, Sbirkov, Yordan, Howell, Louise, Campbell, James, Woster, Patrick M, Poon, Evon, Petrie, Kevin and Chesler, Louis (2021) The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme. Cancer gene therapy. ISSN 1476-5500

Item Type: Article


Deregulated 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. [Abstract copyright: © 2021. The Author(s).]

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Additional Information: ** From PubMed via Jisc Publications Router ** History: received 30-04-2021; revised 09-08-2021; accepted 27-08-2021.
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Item ID: 14077
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ISSN: 1476-5500
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Users with ORCIDS

ORCID for Zuzanna Urban-Wójciuk: ORCID iD
ORCID for Amy Graham: ORCID iD
ORCID for Patrick M Woster: ORCID iD
ORCID for Evon Poon: ORCID iD
ORCID for Kevin Petrie: ORCID iD

Catalogue record

Date Deposited: 04 Nov 2021 11:34
Last Modified: 25 Jan 2022 08:50


Author: Zuzanna Urban-Wójciuk ORCID iD
Author: Amy Graham ORCID iD
Author: Patrick M Woster ORCID iD
Author: Evon Poon ORCID iD
Author: Kevin Petrie ORCID iD
Author: Karen Barker
Author: Colin Kwok
Author: Yordan Sbirkov
Author: Louise Howell
Author: James Campbell
Author: Louis Chesler

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

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