Tubulin acetylation promoting potency and absorption efficacy of deacetylase inhibitors

V. Mangas-Sanjuan, J. Oláh, I. Gonzalez-Alvarez, A. Lehotzky, N. Tokési, M. Bermejo, Judit Ovádi

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE: Histone deacetylase 6 (HDAC6) and silent information regulator 2 (SIRT2) control the dynamics of the microtubule network via their deacetylase activities. Tubulin polymerization promoting protein (TPPP/p25) enhances microtubule acetylation by its direct binding to HDAC6. Our objective was to characterize the multiple interactions of the deacetylases and to establish the inhibitory potency and the pharmacokinetic features of the deacetylase inhibitors, trichostatin A (TSA) and AGK2. EXPERIMENTAL APPROACH: The interactions of deacetylases with tubulin and TPPP/p25 were quantified by ELISA using human recombinant proteins. The effect of inhibitors on the tubulin acetylation was established in HeLa cells transfected with pTPPP and CG-4 cells expressing TPPP/p25 endogenously by CELISA (ELISA on cells), Western blot and immunofluorescence microscopy. The pharmacokinetic features of the inhibitors were evaluated by in situ kinetic modelling of their intestinal transport in rats. KEY RESULTS: Deacetylases interact with both tubulin and TPPP/p25, notwithstanding piggy-back binding of HDAC6 or SIRT2 to the TPPP/p25-associated tubulin was established. Much higher inhibitory potency for TSA than for AGK2 was detected in both HeLa and CG-4 cells. Pioneer pharmacokinetic studies revealed passive diffusion and diffusion coupled with secretion for TSA and AGK2 respectively. Both inhibitors exhibited greater permeability than some other well-established drugs. CONCLUSIONS AND IMPLICATIONS: TPPP/p25-directed deacetylase inhibition provides mechanisms for the fine control of the dynamics and stability of the microtubule network. Deacetylase inhibitors with chemical structures similar to TSA and AGK2 appear to be excellent candidates for oral drug absorption.

Original languageEnglish
Pages (from-to)829-840
Number of pages12
JournalBritish journal of pharmacology
Volume172
Issue number3
DOIs
Publication statusPublished - Feb 2015

ASJC Scopus subject areas

  • Pharmacology

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