Institute of Pharmaceutical Sciences, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
1] Institute of Pharmaceutical Sciences, Albert-Ludwigs-University of Freiburg, Freiburg, Germany [2] Freiburg Institute of Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany.
Oncogenesis. 2015 Feb 9;4(2):e137. doi: 10.1038/oncsis.2014.51.
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.
我们之前描述了新型组蛋白乙酰转移酶（HAT）抑制剂，可在体外阻断神经母细胞瘤细胞生长。在这里，我们展示了两种选定的吡啶并异噻唑酮 HAT 抑制剂 PU139 和 PU141，可诱导细胞组蛋白低乙酰化并抑制源自不同组织的几种肿瘤细胞系的生长。更广泛的体外选择性分析表明，PU139 可阻断 HATs Gcn5、p300/CBP 相关因子（PCAF）、CREB（cAMP 反应元件结合）蛋白（CBP）和 p300，而 PU141 则对 CBP 和 p300 具有选择性。泛抑制剂 PU139 在细胞培养中引发 caspase 非依赖性细胞死亡。两种抑制剂均能阻断 SK-N-SH 神经母细胞瘤异种移植瘤在小鼠中的生长，并且在体内与多柔比星具有协同作用。后者还可降低体内抑制肿瘤异种移植生长的浓度下的组蛋白赖氨酸乙酰化。这是为数不多的具有体内抗癌活性的低乙酰化剂报告之一。
