title: Histone acetyltransferase inhibitors block neuroblastoma cell growth in vivo.
abstract: 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.
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors: J M
authors: JM
authors: Gajer
authors: 1] Institute of Pharmaceutical Sciences, Albert-Ludwigs-University of Freiburg, Freiburg, Germany [2] Freiburg Institute of Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany.
authors: S D
authors: SD
authors: Furdas
authors: Section of Molecular Hematology, Department of Hematology/Oncology, University Hospital Freiburg, Freiburg, Germany.
authors: A
authors: A
authors: Gründer
authors: Section of Molecular Hematology, Department of Hematology/Oncology, University Hospital Freiburg, Freiburg, Germany.
authors: M
authors: M
authors: Gothwal
authors: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
authors: U
authors: U
authors: Heinicke
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors: K
authors: K
authors: Keller
authors: Hybrigenics, 3-5 impasse Reille, Paris, France.
authors: F
authors: F
authors: Colland
authors: 1] Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany [2] German Cancer Consortium (DKTK), Frankfurt, Germany [3] German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: S
authors: S
authors: Fulda
authors: Section of Molecular Hematology, Department of Hematology/Oncology, University Hospital Freiburg, Freiburg, Germany.
authors: H L
authors: HL
authors: Pahl
authors: Experimental Pharmacology and Oncology Berlin-Buch GmbH, Berlin-Buch, Germany.
authors: I
authors: I
authors: Fichtner
authors: 1] Freiburg Institute of Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany [2] Department of Pharmaceutical Chemistry, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany.
authors: W
authors: W
authors: Sippl
authors: 1] Institute of Pharmaceutical Sciences, Albert-Ludwigs-University of Freiburg, Freiburg, Germany [2] German Cancer Consortium (DKTK), Frankfurt, Germany [3] German Cancer Consortium (DKTK), Freiburg, Germany.
authors: M
authors: M
authors: Jung