Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc

被引：92

作者：

Gao, Feng-Hou ^{[2
]}

Hu, Xiao-Hui ^{[2
]}

Li, Wei ^{[3
]}

Liu, Hua ^{[4
]}

Zhang, Yan-Jie ^{[2
]}

Guo, Zhu-Ying ^{[2
]}

Xu, Mang-Hua ^{[2
]}

Wang, Shi-Ting ^{[2
]}

Jiang, Bin ^{[2
]}

Liu, Feng ^{[2
]}

Zhao, Ying-Zheng ^{[3
]}

Fang, Yong ^{[2
]}

Chen, Fang-Yuan ^{[5
]}

Wu, Ying-Li ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Key Lab Cell Differentiat & Apoptosis, Natl Minist Educ, Dept Pathophysiol,Sch Med, Shanghai 200025, Peoples R China

[2] Shanghai Jiao Tong Univ, Peoples Hosp 3, Sch Med, Shanghai 201900, Peoples R China

[3] Wenzhou Med Coll, Sch Life Sci, Zhejiang Prov Key Lab Med Genet, Wenzhou, Zhejiang, Peoples R China

[4] Tongji Univ, Hosp 10, Dept Gastroenterol, Shanghai 200092, Peoples R China

[5] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Shanghai 201900, Peoples R China

来源：

BMC CANCER | 2010年 / 10卷

基金：

中国国家自然科学基金;

关键词：

NF-KAPPA-B; HUMAN BREAST-CANCER; SIGNALING PATHWAYS; RABDOSIA-RUBESCENS; TUMOR-CELLS; IN-VIVO; PROLIFERATION; EXPRESSION; THERAPY; ARREST;

D O I：

10.1186/1471-2407-10-610

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Background: Oridonin, a tetracycline diterpenoid compound, has the potential antitumor activities. Here, we evaluate the antitumor activity and action mechanisms of oridonin in colorectal cancer. Methods: Effects 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 beta-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. Results: Oridonin 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. Conclusion: Oridonin 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.

引用

页数：11

共 42 条

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Development of the pan-DAC inhibitor panobinostat (LBH589): Successes and challenges [J].