Inhibition of histone deacetylases by trans-cinnamic acid and its antitumor effect against colon cancer xenografts in athymic mice.
Inhibition of histone deacetylases by trans-cinnamic acid and its antitumor effect against colon cancer xenografts in athymic mice.
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DOI：
10.3892/mmr.2016.5041
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发表时间：
2016-05
影响因子：
3.4
通讯作者：
Zhen Y
中科院分区：
文献类型：
--
作者：
Zhu B;Shang B;Li Y;Zhen Y
研究表明，反式肉桂酸（trans-cinnamic acid，tCA）具有广泛的生物活性，具有抗氧化、抗炎和抗癌等作用。此外，tCA及其各种类似物已被检测为肠道微生物衍生的代谢产物，在结肠中发挥各种生物学作用。本研究的目的是评估tCA在体外和体内的抗肿瘤活性，特别是其对无胸腺小鼠结肠癌异种移植物的治疗效果。此外，它旨在检查tCA对组蛋白脱乙酰酶（HDAC）的影响，并确定潜在的分子机制。MTT法检测tCA对多种肿瘤细胞的增殖有抑制作用，对HT 29结肠癌细胞的半数抑制浓度（IC50）约为1 mM。Western blot分析表明，tCA可上调乙酰基-H3和乙酰基-H4蛋白的表达，这与HDAC抑制剂曲马多菌素A（TSA）的作用一致。此外，Bcl-2（细胞增殖的标志物）的表达减少，并诱导凋亡。细胞凋亡表现为多聚ADP核糖聚合酶裂解激活和Bax表达增加。还使用APC膜联蛋白V和SYTOX绿色核酸染色证实了细胞凋亡。此外，tCA诱导的HDAC标志物表达的抑制和肿瘤组织中细胞凋亡的激活通过免疫组织化学进一步证实。tCA以1.0和1.5 mmol/kg体重的剂量灌胃给药，在耐受性良好的剂量下抑制了无胸腺小鼠中HT 29人结肠癌异种移植物的生长。组织病理学检查后，在心脏、肺、肝、肾、结肠或骨髓中未发现毒性变化。该研究表明tCA对裸鼠结肠癌异种移植有效。tCA的抗肿瘤机制至少部分通过抑制癌细胞中的HDAC来介导。作为一种主要在结肠中产生的内源性微生物代谢产物，tCA是一种值得进一步评价的药物。
Previous studies have shown that trans-cinnamic acid (tCA) has a broad spectrum of biological activities, and exhibits antioxidant, anti-inflammatory and anticancer properties. In addition, tCA and a variety of its analogs have been detected as gut microbe-derived metabolites exerting various biological effects in the colon. The aim of this study was to assess the antitumor activity of tCA in vitro and in vivo, in particular its therapeutic efficacy against colon cancer xenografts in athymic mice. Furthermore, it aimed to examine the effects of tCA on histone deacetylases (HDACs) and to identify the underlying molecular mechanisms. Using an MTT assay, tCA was observed to inhibit the proliferation of several cancer cell lines, and the half maximal inhibitory concentration (IC50) in HT29 colon carcinoma cells was ~1 mM. Western blot analysis demonstrated that tCA upregulated the expression of acetyl-H3 and acetyl-H4 proteins, which was consistent with the effects of the HDAC inhibitor, trichostatin A (TSA). Furthermore, expression of Bcl-2 (a marker of cell proliferation) was reduced, and apoptosis was induced. Apoptosis was shown by the activation of cleavage of poly ADP ribose polymerase and the increased expression of Bax. Apoptosis was also confirmed using APC Annexin V and SYTOX Green Nucleic Acid Stain. In addition, the tCA-induced inhibition of the expression of HDAC markers and activation of apoptosis in tumor tissues were further confirmed by immunohistochemistry. Intragastric administration of tCA at doses of 1.0 and 1.5 mmol/kg body weight suppressed the growth of HT29 human colon carcinoma xenografts in athymic mice at well-tolerated doses. No toxic changes were found in the heart, lung, liver, kidney, colon or bone marrow following histopathological examination. This study indicated that tCA is effective against colon cancer xenograft in nude mice. The antitumor mechanism of tCA was mediated, at least in part, by inhibition of HDACs in cancer cells. As an endogenous microbial metabolite predominantly produced in the colon, tCA is an agent of interest for further evaluation.