Spermidinyl-CoA-based HAT inhibitors block DNA repair and provide cancer-specific chemo- and radiosensitization.
Spermidinyl-CoA-based HAT inhibitors block DNA repair and provide cancer-specific chemo- and radiosensitization.
复制标题
DOI：
10.4161/cc.8.17.9416
复制
发表时间：
2009-09-01
期刊：
影响因子：
--
通讯作者：
Gjerset RA
中科院分区：
文献类型：
--
作者：
Bandyopadhyay K;Banères JL;Martin A;Blonski C;Parello J;Gjerset RA
核心组蛋白赖氨酸ε-氨基上的乙酰基转换调节DNA可及性功能，而控制这种转换的乙酰化和脱乙酰化酶为抗癌药物的开发提供了重要靶点。组蛋白去乙酰化酶（HDAC）抑制剂已经在临床试验中被广泛开发和评估，而组蛋白乙酰转移酶（HAT）抑制剂的开发进展得更慢。在这里，我们研究了组蛋白乙酰化的S-取代的辅酶A（CoA）抑制剂的细胞效应，由亚精胺（Spd）连接到CoA的S-末端通过巯基乙酸连接（加合物缩写为Spd-CoA），以及缺乏CoA部分的带负电荷的部分的截短的Spd-CoA衍生物的影响。虽然癌细胞暴露于Spd-CoA对细胞活力几乎没有影响，但它会导致组蛋白乙酰化的快速抑制，这与DNA合成的短暂停滞、S期进展的短暂延迟以及核苷酸切除修复和DNA双链断裂修复的抑制相关。这些作用与细胞对DNA靶向化疗药物顺铂（Platinol™）和5-氟尿嘧啶、DNA损伤药物喜树碱和UV-C照射的敏感性增加相关。由于摄取障碍，在正常细胞中未观察到Spd-CoA的致敏作用。截短的Spd-CoA衍生物显示出类似但增强的化学增敏作用，表明Spd-CoA结构的进一步修饰可以进一步提高效力。结果表明，Spd-CoA及其截短的版本被有效地和选择性地内化到癌细胞中，并表明所产生的乙酰化依赖性DNA修复的抑制增强了细胞对DNA损伤的敏感性。因此，这些和相关的组蛋白乙酰化抑制剂可以构成适用于广泛的常规癌症治疗的一类新的有效治疗增敏剂。
Acetyl group turnover on specific lysine ε-amino groups of the core chromosomal histones regulates DNA accessibility function, and the acetylating and deacetylating enzymes that govern the turnover provide important targets for the development of anti-cancer drugs. Histone deacetylase (HDAC) inhibitors have been developed and evaluated extensively in clinical trials, while the development of inhibitors of histone acetyltransferase (HAT) has proceeded more slowly. Here we have examined the cellular effects of an S-substituted coenzyme A (CoA) inhibitor of histone acetylation, consisting of spermidine (Spd) linked to the S-terminus of CoA through a thioglycolic acid linkage (adduct abbreviated as Spd-CoA), as well as the effects of a truncated Spd-CoA derivative lacking the negatively charged portion of the CoA moiety. While exposure of cancer cells to Spd-CoA has little effect on cell viability, it causes a rapid inhibition of histone acetylation that correlates with a transient arrest of DNA synthesis, a transient delay in S-phase progression, and an inhibition of nucleotide excision repair and DNA double strand break repair. These effects correlate with increased cellular sensitivity to the DNA-targeted chemotherapeutic drugs, cisplatin (Platinol™) and 5-fluorouracil, to the DNA damaging drug, camptothecin, and to UV-C irradiation. The sensitization effects of Spd-CoA are not observed in normal cells due to a barrier to uptake. The truncated Spd-CoA derivative displays similar but enhanced chemosensitization effects, suggesting that further modifications of the Spd-CoA structure could further improve potency. The results demonstrate that Spd-CoA and its truncated version are efficiently and selectively internalized into cancer cells, and suggest that the resulting inhibition of acetylation-dependent DNA repair enhances cellular sensitivity to DNA damage. These and related inhibitors of histone acetylation could therefore constitute a novel class of potent therapy sensitizers applicable to a broad range of conventional cancer treatments.
登录
查看更多内容
影响因子：
4.8
作者：
Furuta, T;Takemura, H;Pommier, Y
通讯作者：
Pommier, Y
DOI：
10.1111/j.1432-1033.1981.tb05626.x
发表时间：
1981-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
ESTEPA, I;PESTANA, A
通讯作者：
PESTANA, A
影响因子：
5.3
作者：
AVEMANN, K;KNIPPERS, R;SOGO, JM
通讯作者：
SOGO, JM
DOI：
10.1073/pnas.82.23.8048
发表时间：
1985-01-01
影响因子：
11.1
作者：
ALLIS, CD;CHICOINE, LG;SCHULMAN, IG
通讯作者：
SCHULMAN, IG
影响因子：
20.3
作者：
Deriano, L;Guipaud, O;Delic, J
通讯作者：
Delic, J