Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc.
Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc.
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冬凌草甲素通过增加组蛋白高度乙酰化和 p16、p21、p27 和 c-myc 的调节来诱导结直肠癌细胞凋亡和衰老
DOI：
10.1186/1471-2407-10-610
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发表时间：
2010-11-06
期刊：
影响因子：
3.8
通讯作者：
Wu YL
中科院分区：
文献类型：
--
作者：
Gao FH;Hu XH;Li W;Liu H;Zhang YJ;Guo ZY;Xu MH;Wang ST;Jiang B;Liu F;Zhao YZ;Fang Y;Chen FY;Wu YL
背景冬凌草甲素是一种四环素类二萜化合物，具有潜在的抗肿瘤活性。本研究旨在探讨冬凌草甲素对大肠癌的抗肿瘤作用及其作用机制。方法采用CCK-8试剂盒检测冬凌草甲素对大肠癌细胞增殖的影响。流式细胞仪检测细胞周期分布。通过亚二倍体群体分析和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法检测细胞凋亡。通过衰老相关的β-半乳糖苷酶活性分析来确定衰老细胞。半定量RT-PCR检测p16、p21、p27和c-myc基因mRNA的变化。Western blot分析蛋白质表达的变化。AcH 3和AcH 4的表达通过免疫荧光染色和Western印迹检测。采用软琼脂法检测了冬凌草甲素对SW 1116菌株菌落形成的影响。冬凌草甲素的体内疗效检测使用异种移植大肠癌模型在nukes.ResultsOridonin诱导有效的生长抑制，细胞周期阻滞，凋亡，衰老和集落形成抑制在三个大肠癌细胞系在体外以剂量依赖性的方式。腹腔注射冬凌草甲素（6.25、12.5或25 mg/kg），连续28 d，对SW 1116的生长有明显的抑制作用。在BABL/C裸鼠中的异种移植物。Western blot和RT-PCR进一步证实了冬凌草甲素的抗肿瘤活性与诱导组蛋白表达有关（H3和H4）过度乙酰化，p21、p27和p16的活化，结论冬凌草甲素在体内外均具有较强的抗肿瘤作用，结直肠癌活性与组蛋白过度乙酰化的诱导和维持生长抑制和细胞增殖的关键途径的调节相关。循环停滞因此，冬凌草甲素可能代表一种新的治疗选择，在大肠癌的治疗。
BackgroundOridonin, a tetracycline diterpenoid compound, has the potential antitumor activities. Here, we evaluate the antitumor activity and action mechanisms of oridonin in colorectal cancer.MethodsEffects of oridonin on cell proliferation were determined by using a CCK-8 Kit. Cell cycle distribution was determined by flow cytometry. Apoptosis was examined by analyzing subdiploid population and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Senescent cells were determined by senescence-associated β-galactosidase activity analysis. Semi-quantitative RT-PCR was used to examine the changes of mRNA of p16, p21, p27 and c-myc. The concomitant changes of protein expression were analyzed with Western blot. Expression of AcH3 and AcH4 were examined by immunofluorescence staining and Western blots. Effects of oridonin on colony formation of SW1116 were examined by Soft Agar assay. The in vivo efficacy of oridonin was detected using a xenograft colorectal cancer model in nude mice.ResultsOridonin induced potent growth inhibition, cell cycle arrest, apoptosis, senescence and colony-forming inhibition in three colorectal cancer cell lines in a dose-dependent manner in vitro. Daily i.p. injection of oridonin (6.25, 12.5 or 25 mg/kg) for 28 days significantly inhibited the growth of SW1116 s.c. xenografts in BABL/C nude mice. With western blot and reverse transcription-PCR, we further showed that the antitumor activities of oridonin correlated with induction of histone (H3 and H4) hyperacetylation, activation of p21, p27 and p16, and suppression of c-myc expression.ConclusionOridonin possesses potent in vitro and in vivo anti-colorectal cancer activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell cycle arrest. Therefore, oridonin may represent a novel therapeutic option in colorectal cancer treatment.
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影响因子：
8.8
作者：
Masramon, L;Arribas, R;Tortola, S;Perucho, M;Peinado, M A
通讯作者：
Peinado, M A
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影响因子：
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作者：
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作者：
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影响因子：
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作者：
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