A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth
- Br J Cancer. 2013 Feb 5;108(2):342-50. doi: 10.1038/bjc.2012.576.
- 1. 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.
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.
Conclusion: 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.