Sodium butyrate enhances the cytotoxic effect of cisplatin by abrogating the cisplatin imposed cell cycle arrest.
Sodium butyrate enhances the cytotoxic effect of cisplatin by abrogating the cisplatin imposed cell cycle arrest.
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DOI：
10.1186/1471-2199-11-49
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发表时间：
2010-06-24
影响因子：
--
通讯作者：
Russev G
中科院分区：
文献类型：
--
作者：
Koprinarova M;Markovska P;Iliev I;Anachkova B;Russev G
组蛋白脱乙酰酶抑制剂已被认为是顺铂和其他抗癌药物细胞毒作用的潜在增强剂。它们的应用将允许使用较低的治疗剂量和减少药物的不良副作用。然而，它们使细胞对抗癌药物敏感的分子机制尚不清楚，这是开发有效治疗方案的障碍。在目前的工作中，我们研究了丁酸钠使癌细胞对顺铂增敏的分子机制。HeLa细胞分别用5 mM丁酸盐、8μM顺铂(顺铂)或两者联合作用。与仅用顺铂处理的细胞相比，这两种药物处理的细胞的死亡率大约增加了两倍。因此，与单独使用顺铂相比，用顺铂和丁酸盐治疗感染艾氏腹水瘤的白化小鼠的寿命延长了近两倍。这表明，观察到的顺铂和丁酸盐的协同作用不仅限于特定的细胞系或体外方案，而且在肿瘤发展过程中也在体内表达。DNA标记和荧光激活的细胞分选实验表明，顺铂抑制了DNA的合成，并使HeLa细胞停滞在G1/S过渡期和S早期。Western blotting和染色质免疫沉淀显示，这种作用伴随着组蛋白H4乙酰化水平的降低。丁酸治疗最初通过增加常染色质区域组蛋白H4乙酰化水平来逆转顺铂的作用，常染色质区域负责G1/S相变和DNA合成的启动。这取消了顺铂引起的细胞周期停滞，细胞进入S期，DNA受损。然而，这种影响是暂时的，只持续了几个小时。丁酸盐的长期作用是在异染色质和异染色质中大量的组蛋白乙酰化，抑制DNA复制和细胞凋亡。该研究表明丁酸钠对顺铂的细胞增敏是由于特定染色质区域组蛋白H4的过度乙酰化，从而暂时消除了顺铂引起的细胞周期停滞。
Histone deacetylase inhibitors have been proposed as potential enhancers of the cytotoxic effect of cisplatin and other anticancer drugs. Their application would permit the use of lower therapeutic doses and reduction of the adverse side effects of the drugs. However, the molecular mechanisms by which they sensitize the cells towards anticancer drugs are not known in details, which is an obstacle in developing effective therapeutic protocols. In the present work, we studied the molecular mechanisms by which sodium butyrate sensitizes cancer cells towards cisplatin. HeLa cells were treated with 5 mM butyrate, with 8 μM cis-diaminedichloroplatinum II (cisplatin), or with both. Cells treated with both agents showed approximately two-fold increase of the mortality rate in comparison with cells treated with cisplatin only. Accordingly, the life span of albino mice transfected with Ehrlich ascites tumor was prolonged almost two-fold by treatment with cisplatin and butyrate in comparison with cisplatin alone. This showed that the observed synergism of cisplatin and butyrate was not limited to specific cell lines or in vitro protocols, but was also expressed in vivo during the process of tumor development. DNA labeling and fluorescence activated cell sorting experiments showed that cisplatin treatment inhibited DNA synthesis and arrested HeLa cells at the G1/S transition and early S phase of the cell cycle. Western blotting and chromatin immunoprecipitation revealed that this effect was accompanied with a decrease of histone H4 acetylation levels. Butyrate treatment initially reversed the effect of cisplatin by increasing the levels of histone H4 acetylation in euchromatin regions responsible for the G1/S phase transition and initiation of DNA synthesis. This abrogated the cisplatin imposed cell cycle arrest and the cells traversed S phase with damaged DNA. However, this effect was transient and continued only a few hours. The long-term effect of butyrate was a massive histone acetylation in both eu- and heterochromatin, inhibition of DNA replication and apoptosis. The study presents evidence that cell sensitization towards cisplatin by sodium butyrate is due to hyperacetylation of histone H4 in specific chromatin regions, which temporarily abrogates the cisplatin imposed cell cycle arrest.
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影响因子：
15.9
作者：
Bosco, Emily E.;Wang, Ying;Knudsen, Erik S.
通讯作者：
Knudsen, Erik S.
影响因子：
11.5
作者：
Takai, N;Desmond, JC;Koeffler, HP
通讯作者：
Koeffler, HP
DOI：
10.1073/pnas.95.8.4219
发表时间：
1998-04-14
影响因子：
11.1
作者：
Ishibashi, T;Lippard, SJ
通讯作者：
Lippard, SJ
DOI：
10.1111/j.1432-1033.1996.0489k.x
发表时间：
1996-04-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Tsvetkov, L;Russev, G
通讯作者：
Russev, G
影响因子：
2.3
作者：
Un, Frank
通讯作者：
Un, Frank