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Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models
Author(s) -
Depetter Yves,
Geurs Silke,
De Vreese Rob,
Goethals Sophie,
Vandoorn Elien,
Laevens Alien,
Steenbrugge Jonas,
Meyer Evelyne,
Tullio Pascal,
Bracke Marc,
D'hooghe Matthias,
De Wever Olivier
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32169
Subject(s) - hdac6 , vorinostat , acetylation , in vivo , histone deacetylase , cancer cell , cancer , biology , cancer research , histone , pharmacology , chemistry , biochemistry , genetics , gene
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.