title: Characterisation of the in vitro activity of the depsipeptide histone deacetylase inhibitor spiruchostatin A.
abstract: We recently completed the total synthesis of spiruchostatin A, a depsipeptide natural product with close structural similarities to FK228, a histone deacetylase (HDAC) inhibitor (HDI) currently being evaluated in clinical trials for cancer. Here we report a detailed characterisation of the in vitro activity of spiruchostatin A. Spiruchostatin A was a potent (sub-nM) inhibitor of class I HDAC activity in vitro and acted as a prodrug, requiring reduction for activity. Spiruchostatin A was a potent (low nM) inhibitor of the growth of various cancer cell lines. Spiruchostatin A-induced acetylation of specific lysine residues within histones H3 and H4, and increased the expression of p21(cip1/waf1), but did not induce acetylation of alpha-tubulin. Spiruchostatin A also induced cell cycle arrest, differentiation and cell death in MCF7 breast cancer cells. Like FK228, spiruchostatin A was both an inducer and substrate of the ABCB1 drug efflux pump. Whereas spiruchostatin A and FK228-induced protracted histone acetylation, hydroxamate HDI-induced short-lived histone acetylation. Using a subset of HDI-target genes identified by microarray analysis, we demonstrated that these differences in kinetics of histone acetylation between HDI correlated with differences in the kinetics of induction or repression of specific target genes. Our results demonstrate that spiruchostatin A is a potent inhibitor of class I HDACs and anti-cancer agent. Differences in the kinetics of action of HDI may be important for the clinical application of these compounds.
authors.affiliation: Cancer Research UK Clinical Centre, Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital (MP824), Southampton SO16 6YD, UK. S.J.Crabb@southampton.ac.uk
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Crabb
authors.forename: Melanie
authors.initials: M
authors.lastname: Howell
authors.forename: Helen
authors.initials: H
authors.lastname: Rogers
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ishfaq
authors.forename: Alexander
authors.initials: A
authors.lastname: Yurek-George
authors.forename: Krystle
authors.initials: K
authors.lastname: Carey
authors.forename: Becky M
authors.initials: BM
authors.lastname: Pickering
authors.forename: Phil
authors.initials: P
authors.lastname: East
authors.forename: Richard
authors.initials: R
authors.lastname: Mitter
authors.forename: Satoko
authors.initials: S
authors.lastname: Maeda
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Johnson
authors.forename: Paul
authors.initials: P
authors.lastname: Townsend
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shin-ya
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
mesh_terms: D000107:Acetylation; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D011355:Prodrugs; C485419:spiruchostatin A