Monoketone analogs of curcumin, a new class of Fanconi anemia pathway inhibitors.
Monoketone analogs of curcumin, a new class of Fanconi anemia pathway inhibitors.
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DOI：
10.1186/1476-4598-8-133
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发表时间：
2009-12-31
期刊：
影响因子：
37.3
通讯作者：
Hoatlin ME
中科院分区：
文献类型：
--
作者：
Landais I;Hiddingh S;McCarroll M;Yang C;Sun A;Turker MS;Snyder JP;Hoatlin ME
范可尼贫血（Fanconi anemia， FA）通路是一个多基因DNA损伤反应网络，涉及在复制过程中或外源性DNA损伤后出现的DNA损伤的修复。FA通路显示出与某些DNA修复基因（如ATM (Ataxia telangexasia Mutated)）的合成致死关系，ATM （Ataxia telangexasia Mutated）在肿瘤中经常发生突变。因此，抑制FA通路的关键步骤FANCD2单泛素化（FANCD2- ub）可能通过合成致死相互作用靶向ATM缺陷的肿瘤细胞。姜黄素先前被确定为FANCD2-Ub的弱抑制剂。本研究旨在寻找具有较好活性和特异性的姜黄素衍生物。利用非洲爪蟾提取物的无复制实验，我们筛选了姜黄素的单酮类似物来抑制FANCD2-Ub，并鉴定了类似物EF24是一种强抑制剂。机制研究表明，EF24通过抑制NF-kB通路激酶IKK来靶向FA通路。在HeLa细胞中，纳米摩尔浓度的EF24以不依赖于细胞周期的方式抑制羟基脲（HU）诱导的FANCD2-Ub和病灶。生存试验显示，EF24特异性地使FA-competent细胞对DNA交联剂丝裂霉素C （mitomycin C， MMC）敏感。此外，与姜黄素相比，ATM缺陷细胞对EF24的敏感性是匹配的野生型细胞的两倍，这与FA通路抑制与ATM缺陷之间的合成致死效应一致。一个独立的筛选发现了4H-TTD，这是一种与EF24结构相关的化合物，在鸡蛋提取物和细胞中显示出相似的活性。这些结果表明姜黄素的单酮类似物是FA途径的有效抑制剂，构成了一类有前途的靶向抗癌化合物。
The Fanconi anemia (FA) pathway is a multigene DNA damage response network implicated in the repair of DNA lesions that arise during replication or after exogenous DNA damage. The FA pathway displays synthetic lethal relationship with certain DNA repair genes such as ATM (Ataxia Telangectasia Mutated) that are frequently mutated in tumors. Thus, inhibition of FANCD2 monoubiquitylation (FANCD2-Ub), a key step in the FA pathway, might target tumor cells defective in ATM through synthetic lethal interaction. Curcumin was previously identified as a weak inhibitor of FANCD2-Ub. The aim of this study is to identify derivatives of curcumin with better activity and specificity. Using a replication-free assay in Xenopus extracts, we screened monoketone analogs of curcumin for inhibition of FANCD2-Ub and identified analog EF24 as a strong inhibitor. Mechanistic studies suggest that EF24 targets the FA pathway through inhibition of the NF-kB pathway kinase IKK. In HeLa cells, nanomolar concentrations of EF24 inhibited hydroxyurea (HU)-induced FANCD2-Ub and foci in a cell-cycle independent manner. Survival assays revealed that EF24 specifically sensitizes FA-competent cells to the DNA crosslinking agent mitomycin C (MMC). In addition, in contrast with curcumin, ATM-deficient cells are twofold more sensitive to EF24 than matched wild-type cells, consistent with a synthetic lethal effect between FA pathway inhibition and ATM deficiency. An independent screen identified 4H-TTD, a compound structurally related to EF24 that displays similar activity in egg extracts and in cells. These results suggest that monoketone analogs of curcumin are potent inhibitors of the FA pathway and constitute a promising new class of targeted anticancer compounds.
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