Histone acetyltransferase inhibitors block neuroblastoma cell growth in vivo

We have previously described novel histone acetyltransferase (HAT) inhibitors that block neuroblastoma cell growth in vitro . Here we show that two selected pyridoisothiazolone HAT inhibitors, PU139 and PU141, induce cellular histone hypoacetylation and inhibit growth of several neoplastic cell line...

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Bibliographic Details
Published in:	Oncogenesis (New York, NY) Vol. 4; no. 2; p. e137
Main Authors:	Gajer, J M, Furdas, S D, Gründer, A, Gothwal, M, Heinicke, U, Keller, K, Colland, F, Fulda, S, Pahl, H L, Fichtner, I, Sippl, W, Jung, M
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-02-2015 Nature Publishing Group
Subjects:	631/67/1059/99 631/67/1922 631/80/458/1275 Apoptosis Cell Biology Human Genetics Internal Medicine Medicine Medicine & Public Health Oncology Original original-article
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Summary:	We have previously described novel histone acetyltransferase (HAT) inhibitors that block neuroblastoma cell growth in vitro . Here we show that two selected pyridoisothiazolone HAT inhibitors, PU139 and PU141, induce cellular histone hypoacetylation and inhibit growth of several neoplastic cell lines originating from different tissues. Broader in vitro selectivity profiling shows that PU139 blocks the HATs Gcn5, p300/CBP-associated factor (PCAF), CREB (cAMP response element-binding) protein (CBP) and p300, whereas PU141 is selective toward CBP and p300. The pan-inhibitor PU139 triggers caspase-independent cell death in cell culture. Both inhibitors block growth of SK-N-SH neuroblastoma xenografts in mice and the PU139 was shown to synergize with doxorubicin in vivo . The latter also reduces histone lysine acetylation in vivo at concentrations that block neoplastic xenograft growth. This is one of the very few reports on hypoacetylating agents with in vivo anticancer activity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Oncology Research and Development Unit, Institut de Recherches Servier, 125 Chemin de ronde, 78290 Croissy sur Seine, France These authors contributed equally to the manuscript.
ISSN:	2157-9024 2157-9024
DOI:	10.1038/oncsis.2014.51