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000127368 1001_ $$0P:(DE-HGF)0$$aRettig, I.$$b0$$eFirst author
000127368 245__ $$aSelective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation.
000127368 260__ $$aLondon [u.a.]$$bNature Publishing Group$$c2015
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000127368 520__ $$aFor differentiation-defective malignancies, compounds that modulate transcription, such as retinoic acid and histone deacetylase (HDAC) inhibitors, are of particular interest. HDAC inhibitors are currently under investigation for the treatment of a broad spectrum of cancer diseases. However, one clinical drawback is class-specific toxicity of unselective inhibitors, limiting their full anticancer potential. Selective targeting of individual HDAC isozymes in defined tumor entities may therefore be an attractive alternative treatment approach. We have previously identified HDAC family member 8 (HDAC8) as a novel target in childhood neuroblastoma. Using small-molecule inhibitors, we now demonstrate that selective inhibition of HDAC8 exhibits antineuroblastoma activity without toxicity in two xenograft mouse models of MYCN oncogene-amplified neuroblastoma. In contrast, the unselective HDAC inhibitor vorinostat was more toxic in the same models. HDAC8-selective inhibition induced cell cycle arrest and differentiation in vitro and in vivo. Upon combination with retinoic acid, differentiation was significantly enhanced, as demonstrated by elongated neurofilament-positive neurites and upregulation of NTRK1. Additionally, MYCN oncogene expression was downregulated in vitro and tumor cell growth was markedly reduced in vivo. Mechanistic studies suggest that cAMP-response element-binding protein (CREB) links HDAC8- and retinoic acid-mediated gene transcription. In conclusion, HDAC-selective targeting can be effective in tumors exhibiting HDAC isozyme-dependent tumor growth in vivo and can be combined with differentiation-inducing agents.
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000127368 650_7 $$2NLM Chemicals$$aHistone Deacetylase Inhibitors
000127368 650_7 $$2NLM Chemicals$$aHydroxamic Acids
000127368 650_7 $$2NLM Chemicals$$aIndoles
000127368 650_7 $$2NLM Chemicals$$aPCI 34051
000127368 650_7 $$2NLM Chemicals$$aRepressor Proteins
000127368 650_7 $$05688UTC01R$$2NLM Chemicals$$aTretinoin
000127368 650_7 $$0EC 3.5.1.98$$2NLM Chemicals$$aHDAC8 protein, human
000127368 650_7 $$0EC 3.5.1.98$$2NLM Chemicals$$aHDAC8 protein, mouse
000127368 650_7 $$0EC 3.5.1.98$$2NLM Chemicals$$aHistone Deacetylases
000127368 7001_ $$0P:(DE-He78)700a3a9eaae170adaad6cfbd3d696f93$$aKoeneke, E.$$b1$$udkfz
000127368 7001_ $$0P:(DE-HGF)0$$aTrippel, F.$$b2
000127368 7001_ $$aMueller, W. C.$$b3
000127368 7001_ $$aBurhenne, J.$$b4
000127368 7001_ $$0P:(DE-He78)bb6a7a70f976eb8df1769944bf913596$$aKopp-Schneider, A.$$b5$$udkfz
000127368 7001_ $$0P:(DE-HGF)0$$aFabian, J.$$b6
000127368 7001_ $$aSchober, A.$$b7
000127368 7001_ $$aFernekorn, U.$$b8
000127368 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, A.$$b9$$udkfz
000127368 7001_ $$0P:(DE-HGF)0$$aDeubzer, H. E.$$b10
000127368 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, T.$$b11$$udkfz
000127368 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, O.$$b12$$udkfz
000127368 7001_ $$0P:(DE-He78)908367a659dea9e28dac34592b3c46e5$$aOehme, Ina$$b13$$eLast author$$udkfz
000127368 773__ $$0PERI:(DE-600)2541626-1$$a10.1038/cddis.2015.24$$gVol. 6, no. 2, p. e1657 -$$n2$$pe1657 -$$tCell death & disease$$v6$$x2041-4889$$y2015
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