Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

[en] Our study investigates the biochemical and functional impact of selective histone deacetylase 6 (HDAC6) inhibitors, a promising class of novel therapeutics, in several cancer models. Selective HDAC6 inhibitors (Tubathian A, Tubastatin A, Tubacin and Ricolinostat) and a non-selective HDAC inhibitor (Vorinostat) were evaluated on cancer cell lines derived from multiple tumour types in both an in vitro and in vivo setting as potential cancer therapeutics. Selective HDAC6 inhibitors resulted in α-tubulin acetylation with no impact on histone acetylation but failed to show any anti-cancer properties. Only the use of high concentrations of selective HDAC6 inhibitors resulted in co-inhibition of other HDAC enzymes and consequently in reduced growth, migratory and/or invasive activity of cancer cells in vitro as well as in vivo. The specificity of HDAC6 inhibition was confirmed using a CRISPR/Cas9 knockout cell line. Our results suggest that selective HDAC6 inhibitors may fall short as potential single agent anti-cancer drugs and prove that many previous data regarding this promising class of compounds need to be interpreted with great care due to their use in high concentrations resulting in low selectivity and potential off-target effects.

Disciplines :

Human health sciences: Multidisciplinary, general & others

Author, co-author :

Depetter, Yves; Ghent University > Green chemistry

Geurs, Silke; Ghent University > Green chemistry

De Vreese, Rob; Ghent University > Human structure and repair > Experimental Cancer Research

Goethals, Sophie; Ghent university > Human structure and Repair > Experimental Cancer Research

Vandoorn, Elien; Ghent University > Human structure and repair > Experimental Cancer Research

Steenbrugge, Jonas; Ghent University > Human structure and Repair > Experimental Cancer Research

Meyer, Evelyne; Cancer Research Institute

De Tullio, Pascal ; Université de Liège - ULiège > CIRM > Metabolomics group

Bracke, Marc; Cancer Research Institute Ghent

D'Hooghe, Matthias; Ghent University > Green Chemistry

De Wever, Olivier; Cancer Research Institute Ghent

Language :

English

Title :

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

Publication date :

2019

Journal title :

International Journal of Cancer

ISSN :

0020-7136

eISSN :

1097-0215

Publisher :

John Wiley & Sons, Hoboken, United States - New York

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 24 April 2019

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Bibliography

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