Cu2+ is required for pyrrolidine dithiocarbamate to inhibit histone acetylation and induce human leukemia cell apoptosis
Cu2+ is required for pyrrolidine dithiocarbamate to inhibit histone acetylation and induce human leukemia cell apoptosis
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吡咯烷二硫代氨基甲酸酯抑制组蛋白乙酰化并诱导人白血病细胞凋亡需要 Cu2+。
DOI：
10.1016/j.cbi.2007.09.004
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发表时间：
2008-01-10
影响因子：
5.1
通讯作者：
Wang, Jianmin
中科院分区：
文献类型：
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作者：
Chen, Jie;Du, Changsheng;Wang, Jianmin
吡咯烷二硫代氨基甲酸酯（PDTC）被认为是一种潜在的抗癌药物，因为它对癌细胞具有强大的凋亡作用，其中Cu2+起着独特但尚未明确的作用。在这里，我们报道了Cu2+对于PDTC抑制人白血病HL-60细胞和人肝癌Hep3B细胞中的组蛋白乙酰化至关重要。组蛋白乙酰化的抑制主要是由于细胞内Cu2+的增加，而不是由于PDTC-Cu2+对NF-kappa B活性的抑制，因为Cu2+与SN50、MG132（两种已知的NF-kappa B抑制剂）或二磺酸盐（BCS，一种不穿越质膜的Cu2+特异性螯合剂）联合使用，对组蛋白乙酰化没有明显的抑制作用。组蛋白乙酰转移酶（Histone acetyltransferase， HAT）和组蛋白去乙酰化酶（Histone deacetylase， HDAC）是体内控制组蛋白乙酰化状态的酶。暴露于PDTC-Cu2+的细胞在没有或存在HDAC抑制剂trichostatin a （TSA）或丁酸钠（NaBu）的情况下，HL-60细胞中组蛋白乙酰化水平明显降低；抑制率分别为45%、44%和43%。PDTC-Cu2+在体外对HDAC活性无影响，但在HL-60细胞和体外无细胞系统中均显著抑制HAT活性。PDTC-Cu2+还能诱导HL-60细胞凋亡，TSA、NaBu和BCS均能显著减弱PDTC-Cu2+诱导的细胞凋亡。总的来说，这些结果表明，组蛋白乙酰化的抑制代表了Cu2+存在下PDTC细胞毒性的独特机制，其中HAT是其可能的分子靶点。2007爱思唯尔爱尔兰有限公司版权所有。
Pyrrolidine dithiocarbamate (PDTC) has been considered as a potential anticancer drug due to its powerful apoptogenic effect towards cancer cells, where Cu2+ plays a distinct yet undefined role. Here we report that Cu2+ is critically needed for PDTC to inhibit histone acetylation in both human leukemia HL-60 cells and human hepatoma Hep3B cells. The inhibition of histone acetylation mainly resulted from the increase of intracellular Cu2+, but was not due to the inhibition of NF-kappa B activity by PDTC-Cu2+ since the combinations of Cu2+ with SN50, MG132 (two known NF-kappa B inhibitors), or bathocuproine disulfonate (BCS, a specific Cu2+ chelator that does not cross the plasma membrane), did not lead to obvious inhibition of histone acetylation. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are the enzymes controlling the state of histone acetylation in vivo. Cells exposed to PDTC-Cu2+ showed a comparable decrease in histone acetylation levels in HL-60 cells in the absence or presence of the HDAC inhibitors, trichostatin A (TSA) or sodium butyrate (NaBu); the inhibition rates were about 45, 44 and 43%, respectively. PDTC-Cu2+ had no effect on the activity of HDAC in vitro, but significantly inhibited the HAT activity both in HL-60 cells and in a cell-free in vitro system. PDTC-Cu2+ also induced HL-60 cell apoptosis, and treating cells with TSA, NaBu or BCS significantly attenuated the apoptosis induced by PDTC-Cu2+. Collectively, these results showed that inhibition of histone acetylation represents a distinct mechanism for the cytotoxicity of PDTC in the presence of Cu2+, where HAT is its possible molecular target. (c) 2007 Elsevier Ireland Ltd. All rights reserved.