title: A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth.
abstract: BACKGROUND
  This study investigates whether a histone deacetylase subtype 6 (HDAC6) inhibitor could be used in the treatment of solid tumours.
  
  
  METHODS
  We evaluated the effect of a novel inhibitor, C1A, on HDAC6 biochemical activity and cell growth. We further examined potential of early noninvasive imaging of cell proliferation by [(18)F]fluorothymidine positron emission tomography ([(18)F]FLT-PET) to detect therapy response.
  
  
  RESULTS
  C1A induced sustained acetylation of HDAC6 substrates, α-tubulin and HSP90, compared with current clinically approved HDAC inhibitor SAHA. C1A induced apoptosis and inhibited proliferation of a panel of human tumour cell lines from different origins in the low micromolar range. Systemic administration of the drug inhibited the growth of colon tumours in vivo by 78%. The drug showed restricted activity on gene expression with <0.065% of genes modulated during 24 h of treatment. C1A treatment reduced tumour [(18)F]FLT uptake by 1.7-fold at 48 h, suggesting that molecular imaging could provide value in future studies of this compound.
  
  
  CONCLUSIONS
  C1A preferentially inhibits HDAC6 and modulates HDAC6 downstream targets leading to growth inhibition of a diverse set of cancer cell lines. This property together with the favourable pharmacokinetics and efficacy in vivo makes it a candidate for further pre-clinical and clinical development.
authors: Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer Faculty of Medicine, Imperial College London, Hammersmith Hospital, Room 240, MRC Cyclotron Building, Du Cane Road, London W12 0NN, UK.
authors: M
authors: M
authors: Kaliszczak
authors: S
authors: S
authors: Trousil
authors: O
authors: O
authors: Åberg
authors: M
authors: M
authors: Perumal
authors: Q-D
authors: QD
authors: Nguyen
authors: E O
authors: EO
authors: Aboagye
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D019394:Ki-67 Antigen / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019394:Ki-67 Antigen; D014404:Tubulin; D053148:Caspase 3; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases