组蛋白去乙酰化酶抑制剂——三丁酸甘油酯在结肠癌中的化学预防作用涉及诱导细胞凋亡和减少DNA 损伤

选自：

Toxicology and Applied Pharmacology, Volume 276, Issue 2, 15 April 2014, Pages 129-135

毒理学与应用药理学，第276卷，第2期，2014年4月15日，第129-135页

 

Highlights  亮点

Tributyrin is a chemopreventive agent for rat colon aberrant crypt foci.

三丁酸甘油酯是大鼠结肠异常隐窝灶的化学预防剂。

 

Tributyrin increased apoptosis in an experimental rat colon carcinogenesis model.三丁酸甘油酯在实验性大鼠结肠癌发生模型中增加了细胞凋亡。

 

Tributyrin treatment in a rat colon carcinogenesis model decreased DNA damage.在大鼠结肠癌发生模型中使用三丁酸甘油酯治疗可减少DNA损伤。

 

Tributyrin treatment induced H3K9 acetylation in a rat colon carcinogenesis model.

三丁酸甘油酯可以治疗在大鼠结肠癌发生模型中诱导H3K9乙酰化。

 

PS：高乙酰化水平的H3K9 / K14（H3K9 / K14Ac）是染色体解聚的表观遗传标记和活跃转录的明显信号。

 

Abstract  摘要

The chemopreventive activity of the histone deacetylase inhibitor (HDACi) tributyrin (TB), a prodrug of butyric acid (BA), was evaluated in a rat model of colon carcinogenesis.

在结肠癌发生的大鼠模型中评估了组蛋白去乙酰基化酶抑制剂（HDACi）三丁酸甘油酯（TB）（丁酸的前体物）的化学预防活性。

The animals were treated with TB (TB group: 200 mg/100 g of body weight, b.w.) or maltodextrin (MD isocaloric control group: 300 mg/100 g b.w.) daily for 9 consecutive weeks. In the 3rd and 4th weeks of treatment, the rats in the TB and MD groups were given DMH (40 mg/kg b.w.) twice a week.

分别给予TB (TB组：200 mg/100 g体重)或麦芽糊精(MD等热量对照组：300 mg/100 g体重)治疗，连续9周。在治疗的第3周和第4周，TB组和MD组每周给予DMH (40 mg/kg 体重)两次。

DMH：二甲基肼，诱变剂，科学实验中用于诱导结肠癌。

 

After 9 weeks, the animals were euthanized, and the distal colon was examined. Compared with the control group (MD group), TB treatment reduced the total number of aberrant crypt foci (ACF; p<0.05) as well as the ACF with ≥ 4 crypts (p<0.05), which are considered more aggressive, but not inhibited the formation of DMH-induced O6-methyldeoxyguanosine DNA adducts.

9周后，对动物实施安乐死，并检查远端结肠。与对照组（MD组）相比，TB治疗显著减少了异常隐窝灶的总数（ACF；p<0.05）以及减少被认为更具有攻击性的≥4个隐窝的异常隐窝灶（p<0.05），但并不抑制DMH诱导的脱氧鸟苷DNA加合物的形成。

PS：异常隐窝灶（ACF）被认为是结肠癌发生模型中最早可识别的肿瘤性病变。

 

The TB group also showed a higher apoptotic index (p<0.05) and reduced DNA damage (p<0.05) compared with MD group. TB acted as a HDACi, as rats treated with the prodrug of BA had higher levels of histone H3K9 acetylation compared with the MD group (p<0.05).

与MD组相比，TB组凋亡指数升高(p<0.05)， DNA损伤降低(p<0.05)。TB作为HDACi, BA前体物质组大鼠组蛋白H3K9乙酰化水平高于MD组(p<0.05)。

 

PS：通过测定肿瘤细胞的凋亡指数来评估肿瘤细胞死亡率。

 

TB administration resulted in increased colonic tissue concentrations of BA (p<0.05) compared with the control animals.

与对照动物相比，TB给药导致结肠组织中丁酸浓度升高（p<0.05）。

 

These results suggest that TB can be considered a promising chemopreventive agent for colon carcinogenesis because it reduced the number of ACF, including those that were more aggressive. Induction of apoptosis and reduction of DNA damage are cellular mechanisms that appear to be involved in the chemopreventive activity of TB.

 

这些结果表明，三丁酸甘油酯可以被认为是一种有希望的化学预防结肠癌的物质，因为它减少了ACF的数量，包括那些具攻击性的ACF数量。诱导细胞凋亡和减少DNA损伤似乎是三丁酸甘油酯的化学预防作用的细胞机制。

 

组蛋白去乙酰化酶(histone deacetylase,HDAC)是一类蛋白酶,对染色体的结构修饰和基因表达调控发挥着重要的作用。一般情况下，组蛋白的乙酰化有利于DNA与组蛋白八聚体的解离，核小体结构松弛，从而使各种转录因子和协同转录因子能与DNA结合位点特异性结合，激活基因的转录。而组蛋白的去乙酰化则发挥相反的作用。