Dipartimento di Scienze Ecologiche e Biologiche, University of Tuscia, Via S. Camillo de Lellis snc, 01100 Viterbo Italy.
Curr Med Chem. 2012;19(34):5871-84. doi: 10.2174/092986712804143303.
Four different classes of HDACs have been identified in humans so far. Classes I, II and IV are zinc-dependent amidohydrolases, while III is a family of phylogenetically conserved NAD-dependent protein deacetylases/ADP-ribosyltransferase with a well-defined role in modifying chromatin conformation and altering the accessibility of the damaged sites of DNA for repair enzymes. Sirtuins are histone deacetylases (HDACs) of class III that cleave off acetyl groups from acetyl-lysine residues in histones and non-histone proteins. As sirtuins are involved in many physiological and pathological processes, their activity has been associated with different human diseases, including cancer. Especially two sirtuin members, SIRT1 and SIRT2, have been found to antagonize p53-dependent transcriptional activation and apoptosis in response to DNA damage by catalyzing p53 deacetylation. The findings that SIRT1 levels are increased in a number of tumors highlight the oncogenic role of sirtuins, in particular, in the down-modulation of p53 oncosuppressor activity. Along this lane, cancers carrying wild-type (wt) p53 protein are known to deregulate its activity by other mechanisms. Therefore, inhibition of SIRT1 and SIRT2, aimed at restoring wt-p53 transcriptional activity in tumors that retain the ability to express normal p53, might represent a valid therapeutic cancer approach specially when combined with standard therapies. This review will be focused on sirtuin inhibitors, with a specific attention on inhibitors of SIRT1 and SIRT2. Among them, nicotinamide and its analogs, sirtinol, A3 and M15, splitomicin, HR73 and derivatives, cambinol and derivatives, EX 527, kinase inhibitors, suramin, 4-dihydropyridine derivatives, tenovins, TRIPOS 360702, AC 93253, 3-arylideneindolinones, CSC8 and CSC13 will also be described.
迄今为止，人类已经鉴定出四类 HDAC。I 类、II 类和 IV 类是锌依赖性酰胺水解酶，而 III 类是一类进化上保守的 NAD 依赖性蛋白去乙酰化酶/ADP-核糖基转移酶，其在修饰染色质构象和改变 DNA 损伤部位的修复酶可及性方面具有明确的作用。Sirtuins 是 III 类组蛋白去乙酰化酶（HDAC），能够从组蛋白和非组蛋白蛋白的乙酰化赖氨酸残基上切割出乙酰基。由于 Sirtuins 参与了许多生理和病理过程，其活性与包括癌症在内的多种人类疾病有关。特别是两个 Sirtuin 成员 SIRT1 和 SIRT2 被发现通过催化 p53 去乙酰化来拮抗 DNA 损伤诱导的 p53 依赖性转录激活和细胞凋亡。许多肿瘤中 SIRT1 水平升高的发现强调了 Sirtuins 的致癌作用，特别是在下调 p53 肿瘤抑制活性方面。沿着这条途径，携带野生型（wt）p53 蛋白的癌症通过其他机制使其活性失调。因此，抑制 SIRT1 和 SIRT2，旨在恢复保留表达正常 p53 能力的肿瘤中的 wt-p53 转录活性，可能代表一种有效的治疗癌症方法，特别是与标准疗法联合使用时。这篇综述将重点介绍 Sirtuin 抑制剂，特别关注 SIRT1 和 SIRT2 的抑制剂。其中，烟酰胺及其类似物、sirtinol、A3 和 M15、splitomicin、HR73 和衍生物、cambinol 和衍生物、EX 527、激酶抑制剂、苏拉明、4-二氢吡啶衍生物、tenovins、TRIPOS 360702、AC 93253、3-亚芳基吲哚啉酮、CSC8 和 CSC13 也将被描述。
