Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes
Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes
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DOI：
10.1158/0008-5472.can-05-3617
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发表时间：
2006-04-15
期刊：
影响因子：
11.2
通讯作者：
Bedalov, A
中科院分区：
文献类型：
--
作者：
Heltweg, B;Gatbonton, T;Bedalov, A
SIRT1 和其他 NAD 依赖性脱乙酰酶通过重要调节蛋白（包括 p53 和 BCL6 癌蛋白）的脱乙酰作用参与控制细胞对应激的反应和肿瘤发生。在此，我们描述了一种我们命名为 Cambinol 的化合物的鉴定，该化合物抑制人 SIRT1 和 SIRT2 的 NAD 依赖性脱乙酰酶活性。与 SIRT1 在应激期间促进细胞存活的作用一致，在基因毒性应激期间用 Cambinol 抑制 SIRT1 活性会导致关键应激反应蛋白的过度乙酰化并促进细胞周期停滞。用cambinol作为单一药物处理表达BCL6的Burkitt淋巴瘤细胞可诱导细胞凋亡，并伴有BCL6和p53的高度乙酰化。由于乙酰化会使 BCL6 失活，并对 p53 和其他检查点通路的功能产生相反的影响，因此 Cambinol 在 Burkitt 淋巴瘤细胞中的抗肿瘤活性可能是通过 BCL6 失活和检查点激活的联合作用来实现的。 Cambinol 在小鼠中具有良好的耐受性，并能抑制伯基特淋巴瘤异种移植物的生长。 NAD 依赖性脱乙酰酶抑制剂可能构成新型抗癌药物。
SIRT1 and other NAD-dependent deacetylases have been implicated in control of cellular responses to stress and in tumorigenesis through deacetylation of important regulatory proteins, including p53 and the BCL6 oncoprotein. Hereby, we describe the identification of a compound we named cambinol that inhibits NAD-dependent deacetylase activity of human SIRT1 and SIRT2. Consistent with the role of SIRT1 in promoting cell survival during stress, inhibition of SIRT1 activity with cambinol during genotoxic stress leads to hyperacetylation of key stress response proteins and promotes cell cycle arrest. Treatment of BCL6-expressing Burkitt lymphoma cells with cambinol as a single agent induced apoptosis, which was accompanied by hyperacetylation of BCL6 and p53. Because acetylation inactivates BCL6 and has the opposite effect on the function of p53 and other checkpoint pathways, the antitumor activity of cambinol in Burkitt lymphoma cells may be accomplished through a combined effect of BCL6 inactivation and checkpoint activation. Cambinol was well tolerated in mice and inhibited growth of Burkitt lymphoma xenografts. Inhibitors of NAD-dependent deacetylases may constitute novel anticancer agents.