Article

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

Details

Citation

Urban-Wójciuk Z, Graham A, Barker K, Kwok C, Sbirkov Y, Howell L, Campbell J, Woster PM, Poon E, Petrie K & Chesler L (2022) The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme. Cancer Gene Therapy, 29, pp. 940-950. https://doi.org/10.1038/s41417-021-00386-6

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.

Keywords
Paediatric cancer; Targeted therapies

Journal
Cancer Gene Therapy: Volume 29

StatusPublished
FundersCancer Research UK and European Commission (Horizon 2020)
Publication date31/07/2022
Publication date online30/09/2021
Date accepted by journal27/08/2021
URLhttp://hdl.handle.net/1893/33392
ISSN0929-1903
eISSN1476-5500