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A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth.
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2013 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, no 2, 342-50 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2013. Vol. 108, no 2, 342-50 p.
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Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-202006DOI: 10.1038/bjc.2012.576PubMedID: 23322205OAI: oai:DiVA.org:uu-202006DiVA: diva2:630379
Available from: 2013-06-18 Created: 2013-06-18 Last updated: 2017-12-06

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Publisher's full textPubMedhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566806/http://www.nature.com/bjc/journal/v108/n2/full/bjc2012576a.html

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Åberg, O

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