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

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Abstract

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).]

Item Type: Article
Additional Information: ** From PubMed via Jisc Publications Router ** History: received 30-04-2021; revised 09-08-2021; accepted 27-08-2021.
Divisions: Faculty of Health Sciences and Wellbeing > School of Medicine
SWORD Depositor: Publication Router
Depositing User: Publication Router
Date Deposited: 04 Nov 2021 11:34
Last Modified: 04 Nov 2021 11:34
URI: http://sure.sunderland.ac.uk/id/eprint/14077
ORCID for Zuzanna Urban-Wójciuk: ORCID iD orcid.org/0000-0002-5868-1991
ORCID for Amy Graham: ORCID iD orcid.org/0000-0002-2196-8374
ORCID for Patrick M Woster: ORCID iD orcid.org/0000-0002-9471-1916
ORCID for Evon Poon: ORCID iD orcid.org/0000-0002-0616-2487
ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

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