title: Acquired vorinostat resistance shows partial cross-resistance to 'second-generation' HDAC inhibitors and correlates with loss of histone acetylation and apoptosis but not with altered HDAC and HAT activities.
abstract: Histone deacetylase (HDAC) inhibitors such as vorinostat (suberoylanilide hydroxamic acid), valproic acid, romidepsin (FK-228), and LBH589 comprise a relatively new class of potent anticancer agents. This study provides evidence for the potential of vorinostat to cause acquisition of multidrug resistance protein-independent resistance in HCT116 colon tumor cells. This acquired resistance is moderate (two-fold to three-fold), is nonreversible, and correlates with the loss of responses typically seen with HDAC inhibitors, that is the loss of acetylation of the histones H2A, H2B, H3, and H4, the loss of the G2/M checkpoint activation, and the loss of caspase 3-dependent and caspase 7-dependent apoptosis. This acquired resistance also associates with cross-resistance to the hydroxamate-class (LBH589 and JNJ26481585) and to the aliphatic acid-class (valproic acid) HDAC inhibitors but not to the benzamide-class (MGCD0103) and the cyclic peptide-class (romidepsin) HDAC inhibitors. The acquired HDAC inhibitor resistance described hereis not a result of altered HDAC and histone acetyltransferase activities and differs from that previously reported for romidepsin.
authors.affiliation: Department of Gynecology, University Hospital Zurich bDivision of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Konstantin J
authors.initials: KJ
authors.lastname: Dedes
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dedes
authors.forename: Patrick
authors.initials: P
authors.lastname: Imesch
authors.forename: André O
authors.initials: AO
authors.lastname: von Bueren
authors.forename: Daniel
authors.initials: D
authors.lastname: Fink
authors.forename: André
authors.initials: A
authors.lastname: Fedier