Betulinic Acid Suppresses Ovarian Cancer Cell Proliferation through Induction of Apoptosis
Betulinic Acid Suppresses Ovarian Cancer Cell Proliferation through Induction of Apoptosis
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DOI：
10.3390/biom9070257
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发表时间：
2019-07-01
期刊：
影响因子：
5.5
通讯作者：
Kim, Ki Hyun
中科院分区：
文献类型：
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作者：
Lee, Dahae;Lee, Seoung Rak;Kim, Ki Hyun
卵巢癌是全世界妇女癌症死亡的主要原因之一，也是各种妇科癌症中最恶性的癌症。在这项研究中，我们从山茱萸（Cornus walteri） （Cornaceae）中探索了潜在的抗癌化合物，其MeOH提取物已被报道对几种癌细胞表现出相当大的细胞毒性。通过广泛应用色谱技术对华氏藤茎和茎皮的MeOH提取物进行植物化学研究，分离出14种化合物（1-14）。研究了分离得到的化合物对人卵巢癌细胞A2780的抑制作用，并探讨了其分子机制。采用3-（4,5-二甲基噻唑-2-酰基）-2,5-二苯基溴化四唑（MTT）法检测化合物1-14对A2780细胞的抗癌作用，结果表明化合物11（白桦酸）对A2780细胞的活性呈浓度依赖性降低，24 h时IC50最大（50%）为44.47 μ M。白桦酸显著提高A2780细胞的核凝聚率和凋亡细胞百分比，并呈浓度依赖性。Western blot检测细胞凋亡的机制。结果表明，在白桦酸处理的A2780细胞中，cleaved caspase-8、-3、-9和Bax的表达水平升高，而Bcl-2的表达水平降低。因此，我们提供了实验证据，证明白桦酸可以通过线粒体依赖性和非依赖性途径诱导A2780细胞凋亡，并提示白桦酸在卵巢癌治疗新化疗药物开发中的潜在应用。
Ovarian cancer is one of the leading causes of cancer deaths worldwide in women, and the most malignant cancer among the different gynecological cancers. In this study, we explored potentially anticancer compounds from Cornus walteri (Cornaceae), the MeOH extract of which has been reported to show considerable cytotoxicity against several cancer cell lines. Phytochemical investigations of the MeOH extract of the stem and stem bark of C. walteri by extensive application of chromatographic techniques resulted in the isolation of 14 compounds (1-14). The isolated compounds were evaluated for inhibitory effects on the viability of A2780 human ovarian carcinoma cells and the underlying molecular mechanisms were investigated. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was employed to assess the anticancer effects of compounds 1-14 on A2780 cells, which showed that compound 11 (betulinic acid) reduced the viability of these cells in a concentration-dependent manner and had an half maximal (50%) inhibitory concentration (IC50) of 44.47 mu M at 24 h. Nuclear staining and image-based cytometric assay were carried out to detect the induction of apoptosis by betulinic acid. Betulinic acid significantly increased the condensation of nuclei and the percentage of apoptotic cells in a concentration-dependent manner in A2780 cells. Western blot analysis was performed to investigate the underlying mechanism of apoptosis. The results indicated that the expression levels of cleaved caspase-8, -3, -9, and Bax were increased in A2780 cells treated with betulinic acid, whereas those of Bcl-2 were decreased. Thus, we provide the experimental evidence that betulinic acid can induce apoptosis in A2780 cells through both mitochondria-dependent and -independent pathways and suggest the potential use of betulinic acid in the development of novel chemotherapeutics for ovarian cancer therapy.