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  5. Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor
 
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Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor

Author(s)
Sundaramurthi, Husvinee  
García-Mulero, Sandra  
Tonelotto, Valentina  
Slater, Kayleigh  
Marcone, Simone  
Piulats, J. M.  
Watson, R. William  
Tobin, Desmond John  
Jensen, Lasse D.  
Kennedy, Breandán  
Uri
http://hdl.handle.net/10197/13201
Date Issued
2022-02-03
Date Available
2022-10-14T15:46:35Z
Abstract
Metastatic uveal melanoma (MUM) is characterized by poor patient survival. Unfortunately, current treatment options demonstrate limited benefits. In this study, we evaluate the efficacy of ACY-1215, a histone deacetylase inhibitor (HDACi), to attenuate growth of primary ocular UM cell lines and, in particular, a liver MUM cell line in vitro and in vivo, and elucidate the underlying molecular mechanisms. A significant (p = 0.0001) dose-dependent reduction in surviving clones of the primary ocular UM cells, Mel270, was observed upon treatment with increasing doses of ACY-1215. Treatment of OMM2.5 MUM cells with ACY-1215 resulted in a significant (p = 0.0001), dose-dependent reduction in cell survival and proliferation in vitro, and in vivo attenuation of primary OMM2.5 xenografts in zebrafish larvae. Furthermore, flow cytometry revealed that ACY-1215 significantly arrested the OMM2.5 cell cycle in S phase (p = 0.0001) following 24 h of treatment, and significant apoptosis was triggered in a time-and dose-dependent manner (p < 0.0001). Additionally, ACY-1215 treatment resulted in a significant reduction in OMM2.5 p-ERK expression levels. Through proteome profiling, the attenuation of the microphthalmia-associated transcription factor (MITF) signaling pathway was linked to the observed anti-cancer effects of ACY-1215. In agreement, pharmacological inhibition of MITF signaling with ML329 significantly reduced OMM2.5 cell survival and viability in vitro (p = 0.0001) and reduced OMM2.5 cells in vivo (p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of OMM2.5 MUM cells.
Sponsorship
European Commission Horizon 2020
Other Sponsorship
Research Council—Enterprise Partnership Scheme 2020
Breakthrough Cancer Research
TopMed10—Marie Skłodowska-Curie Actions COFUND Programme
Type of Material
Journal Article
Publisher
MDPI
Journal
Cancers
Volume
14
Issue
3
Start Page
1
End Page
31
Copyright (Published Version)
2022 The Authors
Subjects

Metastatic uveal mela...

HDAC inhibitor

ACY-1215

MITF

p-ERK

ML329

Zebrafish xenografts

DOI
10.3390/cancers14030782
Language
English
Status of Item
Peer reviewed
ISSN
2072-6694
This item is made available under a Creative Commons License
https://creativecommons.org/licenses/by/3.0/ie/
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Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor. .pdf

Size

5.2 MB

Format

Adobe PDF

Checksum (MD5)

9fc356404d0afe8100df5580d19a68a4

Owning collection
Biomolecular and Biomedical Science Research Collection
Mapped collections
Conway Institute Research Collection•
Medicine Research Collection•
SBI Research Collection

Item descriptive metadata is released under a CC-0 (public domain) license: https://creativecommons.org/public-domain/cc0/.
All other content is subject to copyright.

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