Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Mol Cancer Ther. 2013 Apr;12(4):352-60. doi: 10.1158/1535-7163.MCT-12-0900. Epub 2013 Jan 15.
While small-molecule inhibitors of class I/II histone deacetylases (HDAC) have been approved for cancer treatment, inhibitors of the sirtuins (a family of class III HDACs) still require further validation and optimization to enter clinical trials. Recent studies show that tenovin-6, a small-molecule inhibitor of sirtuins SirT1 and SirT2, reduces tumor growth in vivo and eliminates leukemic stem cells in a murine model for chronic myelogenous leukemia. Here, we describe a tenovin analogue, tenovin-D3, that preferentially inhibits sirtuin SirT2 and induces predicted phenotypes for SirT2 inhibition. Unlike tenovin-6 and in agreement with its weak effect on SirT1 (a p53 deacetylase), tenovin-D3 fails to increase p53 levels or transcription factor activity. However, tenovin-D3 promotes expression of the cell-cycle regulator and p53 target p21(WAF1/CIP1) (CDKN1A) in a p53-independent manner. Structure-activity relationship studies strongly support that the ability of tenovin-D3 to inhibit SirT2 contributes to this p53-independent induction of p21. The ability of tenovin-D3 to increase p21 mRNA and protein levels is shared with class I/II HDAC inhibitors currently used in the clinic and therefore suggests that SirT2 inhibition and class I/II HDAC inhibitors have similar effects on cell-cycle progression.
虽然 I/II 类组蛋白去乙酰化酶（HDAC）的小分子抑制剂已被批准用于癌症治疗，但 sirtuins（III 类 HDAC 家族）的抑制剂仍需要进一步验证和优化才能进入临床试验。最近的研究表明，小分子 sirtuins SirT1 和 SirT2 抑制剂 tenovin-6 可减少体内肿瘤生长，并在慢性粒细胞白血病的小鼠模型中消除白血病干细胞。在这里，我们描述了 tenovin 的类似物 tenovin-D3，它优先抑制 sirtuin SirT2 并诱导出 SirT2 抑制的预测表型。与 tenovin-6 不同，并且与其对 SirT1（p53 去乙酰化酶）的弱作用一致，tenovin-D3 不会增加 p53 水平或转录因子活性。然而，tenovin-D3 以 p53 非依赖性方式促进细胞周期调节剂和 p53 靶标 p21(WAF1/CIP1)（CDKN1A）的表达。结构-活性关系研究强烈支持 tenovin-D3 抑制 SirT2 的能力有助于这种 p53 非依赖性诱导 p21。tenovin-D3 增加 p21 mRNA 和蛋白水平的能力与目前临床上使用的 I/II 类 HDAC 抑制剂共享，因此表明 SirT2 抑制和 I/II 类 HDAC 抑制剂对细胞周期进程具有相似的作用。
