Metabolic Effects of Known and Novel HDAC and SIRT Inhibitors in Glioblastomas Independently or Combined with Temozolomide.
Metabolic Effects of Known and Novel HDAC and SIRT Inhibitors in Glioblastomas Independently or Combined with Temozolomide.
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DOI：
10.3390/metabo4030807
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发表时间：
2014-09-12
期刊：
影响因子：
4.1
通讯作者：
Culf AS
中科院分区：
文献类型：
--
作者：
Cuperlovic-Culf M;Touaibia M;St-Coeur PD;Poitras J;Morin P;Culf AS
单独或与标准化疗联合抑制蛋白质脱乙酰化酶是癌症治疗的一个令人兴奋的补充。我们研究了去乙酰化酶抑制剂对胶质母细胞瘤细胞代谢的影响。使用1H NMR代谢组学分析来确定用五种不同的组蛋白脱乙酰酶（HDAC）抑制剂以及一种NAD+依赖性蛋白脱乙酰酶（SIRT）抑制剂处理两种不同的胶质母细胞瘤细胞系U373和LN 229后的主要代谢变化。在HDAC和SIRT治疗中加入标准的胶质母细胞瘤化疗药物替莫唑胺导致细胞存活率降低，这表明联合治疗的可能性。这项研究表明，不同的胶质母细胞瘤细胞系，具有不同的代谢谱和基因表达，经历不同的变化后，与蛋白脱乙酰酶抑制剂治疗。所观察到的抑制剂对线粒体代谢、糖酵解和脂肪酸合成的影响表明蛋白质脱乙酰酶在代谢调节中可能起作用。已经探索了抗蛋白脱乙酰酶治疗有效性的代谢标志物。除了已知的脱乙酰化抑制剂，三种新的抑制剂已被引入和测试。最后，细胞代谢的1H NMR分析被证明是测试药物作用的快速、廉价的方法。
Inhibition of protein deacetylation enzymes, alone or in combination with standard chemotherapies, is an exciting addition to cancer therapy. We have investigated the effect of deacetylase inhibition on the metabolism of glioblastoma cells. 1H NMR metabolomics analysis was used to determine the major metabolic changes following treatment of two distinct glioblastoma cell lines, U373 and LN229, with five different histone deacetylase (HDAC) inhibitors, as well as one inhibitor of NAD+-dependent protein deacetylases (SIRT). The addition of the standard glioblastoma chemotherapy agent, temozolomide, to the HDAC and SIRT treatments led to a reduction in cell survival, suggesting a possibility for combined treatment. This study shows that distinct glioblastoma cell lines, with different metabolic profiles and gene expression, experience dissimilar changes following treatment with protein deacetylase inhibitors. The observed effects of inhibitors on mitochondrial metabolism, glycolysis and fatty acid synthesis suggest possible roles of protein deacetylases in metabolism regulation. Metabolic markers of the effectiveness of anti-protein deacetylase treatments have been explored. In addition to known deacetylation inhibitors, three novel inhibitors have been introduced and tested. Finally, 1H NMR analysis of cellular metabolism is shown to be a fast, inexpensive method for testing drug effects.