Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect
Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect
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DOI：
10.1038/onc.2008.436
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发表时间：
2009-02-01
期刊：
影响因子：
8
通讯作者：
Fraga, M. F.
中科院分区：
文献类型：
--
作者：
Lara, E.;Mai, A.;Fraga, M. F.
Sirtuin 1(Sirt1)和Sirtuin 2(SIRT2)属于NAD+(烟酰胺腺嘌呤二核苷酸阳性)依赖的III类组蛋白脱乙酰酶家族，参与调节寿命。由于癌症是一种老年性疾病，靶向sirtuins正在成为一种有前途的抗癌策略。在这里，我们介绍了舒乐胺(N-{3-[(2-hydroxynaphthalen-1-ylmethylene)-amino]-phenyl}-2-phenyl-propionamide)，，一种反转胺，在体外对sirt1和sirt2有很强的抑制作用。沙勒胺在小鼠体内的耐受性很好，浓度高达100亩M，并在广泛的人类癌细胞系中促进肿瘤特异性细胞死亡。沙乐胺的抗肿瘤活性主要是因为大量诱导细胞凋亡。这不依赖于全局微管蛋白和K16H4乙酰化，这排除了SIRT2介导的凋亡途径，并暗示了通过Sirt1的体内作用机制。与此一致的是，RNA干扰介导的Sirt1基因敲除，而不是SIRT2基因敲除，诱导了癌细胞的凋亡。虽然P53已被报道为Sirt1的靶点，但基因上的P53基因敲除表明，沙乐胺依赖Sirt1的促凋亡作用不依赖于P53。我们终于能够将沙勒胺的促凋亡作用归因于Sirt1在癌细胞中仅在表观遗传学上抑制的促凋亡基因的重新激活。综上所述，我们的结果强调了沙乐胺作为一种抗癌药物的前景，并为Sirt1参与人类肿瘤发生的分子机制提供了证据。
Sirtuin 1 (Sirt1) and Sirtuin 2 (Sirt2) belong to the family of NAD+(nicotinamide adenine dinucleotide-positive)dependent class III histone deacetylases and are involved in regulating lifespan. As cancer is a disease of ageing, targeting Sirtuins is emerging as a promising antitumour strategy. Here we present Salermide (N-{3-[(2-hydroxynaphthalen-1-ylmethylene)-amino]-phenyl}-2-phenyl-propionamide), a reverse amide with a strong in vitro inhibitory effect on Sirt1 and Sirt2. Salermide was well tolerated by mice at concentrations up to 100 mu M and prompted tumour-specific cell death in a wide range of human cancer cell lines. The antitumour activity of Salermide was primarily because of a massive induction of apoptosis. This was independent of global tubulin and K16H4 acetylation, which ruled out a putative Sirt2-mediated apoptotic pathway and suggested an in vivo mechanism of action through Sirt1. Consistently with this, RNA interference-mediated knockdown of Sirt1, but not Sirt2, induced apoptosis in cancer cells. Although p53 has been reported to be a target of Sirt1, genetic p53 knockdowns showed that the Sirt1-dependent proapoptotic effect of Salermide is p53-independent. We were finally able to ascribe the apoptotic effect of Salermide to the reactivation of proapoptotic genes epigenetically repressed exclusively in cancer cells by Sirt1. Taken together, our results underline Salermide's promise as an anticancer drug and provide evidence for the molecular mechanism through which Sirt1 is involved in human tumorigenesis.