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@ARTICLE{Rettig:127368,
author = {I. Rettig$^*$ and E. Koeneke$^*$ and F. Trippel$^*$ and W.
C. Mueller and J. Burhenne and A. Kopp-Schneider$^*$ and J.
Fabian$^*$ and A. Schober and U. Fernekorn and A. von
Deimling$^*$ and H. E. Deubzer$^*$ and T. Milde$^*$ and O.
Witt$^*$ and I. Oehme$^*$},
title = {{S}elective inhibition of {HDAC}8 decreases neuroblastoma
growth in vitro and in vivo and enhances retinoic
acid-mediated differentiation.},
journal = {Cell death $\&$ disease},
volume = {6},
number = {2},
issn = {2041-4889},
address = {London [u.a.]},
publisher = {Nature Publishing Group},
reportid = {DKFZ-2017-03393},
pages = {e1657 -},
year = {2015},
abstract = {For differentiation-defective malignancies, compounds that
modulate transcription, such as retinoic acid and histone
deacetylase (HDAC) inhibitors, are of particular interest.
HDAC inhibitors are currently under investigation for the
treatment of a broad spectrum of cancer diseases. However,
one clinical drawback is class-specific toxicity of
unselective inhibitors, limiting their full anticancer
potential. Selective targeting of individual HDAC isozymes
in defined tumor entities may therefore be an attractive
alternative treatment approach. We have previously
identified HDAC family member 8 (HDAC8) as a novel target in
childhood neuroblastoma. Using small-molecule inhibitors, we
now demonstrate that selective inhibition of HDAC8 exhibits
antineuroblastoma activity without toxicity in two xenograft
mouse models of MYCN oncogene-amplified neuroblastoma. In
contrast, the unselective HDAC inhibitor vorinostat was more
toxic in the same models. HDAC8-selective inhibition induced
cell cycle arrest and differentiation in vitro and in vivo.
Upon combination with retinoic acid, differentiation was
significantly enhanced, as demonstrated by elongated
neurofilament-positive neurites and upregulation of NTRK1.
Additionally, MYCN oncogene expression was downregulated in
vitro and tumor cell growth was markedly reduced in vivo.
Mechanistic studies suggest that cAMP-response
element-binding protein (CREB) links HDAC8- and retinoic
acid-mediated gene transcription. In conclusion,
HDAC-selective targeting can be effective in tumors
exhibiting HDAC isozyme-dependent tumor growth in vivo and
can be combined with differentiation-inducing agents.},
keywords = {Histone Deacetylase Inhibitors (NLM Chemicals) / Hydroxamic
Acids (NLM Chemicals) / Indoles (NLM Chemicals) / PCI 34051
(NLM Chemicals) / Repressor Proteins (NLM Chemicals) /
Tretinoin (NLM Chemicals) / HDAC8 protein, human (NLM
Chemicals) / HDAC8 protein, mouse (NLM Chemicals) / Histone
Deacetylases (NLM Chemicals)},
cin = {G340 / C060 / G380},
ddc = {570},
cid = {I:(DE-He78)G340-20160331 / I:(DE-He78)C060-20160331 /
I:(DE-He78)G380-20160331},
pnm = {317 - Translational cancer research (POF3-317)},
pid = {G:(DE-HGF)POF3-317},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25695609},
pmc = {pmc:PMC4669789},
doi = {10.1038/cddis.2015.24},
url = {https://inrepo02.dkfz.de/record/127368},
}