Key Laboratory of the Laboratory of Medical Diagnostics, Ministry of Education, Chongqing Key Laboratory, Faculty of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Planta Med. 2010 Sep;76(13):1447-53. doi: 10.1055/s-0029-1240902. Epub 2010 Feb 15.
Toosendanin, a triterpenoid derivative isolated from Melia toosendan Sieb. et Zucc., possesses different pharmacological effects in humans and an important value in agriculture. As indicated by previous reports, the molecular mechanisms of toosendanin's anticancer effects remain poorly clarified. In this study we used both in vivo and in vitro models to investigate the anti-cancer effects of toosendanin and their possible molecular mechanisms. In the in vitro experiment, human hepatocellular carcinoma cell lines [SMMC-7721(p53+) and Hep3B (p53-)] were coincubated with toosendanin of different concentrations (0.1~ 0.9 µM). Anti-proliferation effects were observed to be in a dose- and time-dependent manner. The IC(50) of TSN treated after 72 h for SMMC-7721 and Hep3B cells was 0.5 µM and 0.9 µM, respectively. Results from morphological analysis, annexin V staining, detection of caspases activity, and expressions of Bcl-2, Bax, and Fas indicated that the anticancer effects of toosendanin were associated with its induction of apoptosis via the mitochondria-dependent pathway in p53- and p53+ hepatocellular carcinoma cells. In the IN VIVO experiment, BALB/c mice were s.c. inoculated with mouse hepatocellular carcinoma H (22) cells. Both high-dose (0.69 mg/kg) and low-dose (0.173 mg/kg) toosendanin administrated intraperitoneally resulted in strongly suppressive effects on the tumorigenicity and apoptotic response. Results from the immunohistochemistry for Bcl-2, Bax, as well as for Fas showed that the anticancer effects of toosendanin were induced via apoptosis in a mitochondria-dependent manner, which confirmed the findings in the in vitro experiment. The findings above demonstrate that toosendanin possesses strong anticancer effects in vivo and in vitro via inducing mitochondria-dependent apoptosis in hepatocellular carcinoma cells.
川楝素是从川楝（Melia toosendan Sieb. et Zucc.）中分离得到的一种三萜类衍生物，在人类中具有不同的药理作用，在农业中有重要价值。如前所述，川楝素的抗癌作用的分子机制仍不清楚。在这项研究中，我们使用体内和体外模型来研究川楝素的抗癌作用及其可能的分子机制。在体外实验中，将人肝癌细胞系[SMMC-7721（p53+）和 Hep3B（p53-）]与不同浓度（0.1~0.9 μM）的川楝素共同孵育。观察到抗增殖作用呈剂量和时间依赖性。TSN 处理后 72 h 的 SMMC-7721 和 Hep3B 细胞的 IC50 分别为 0.5 μM 和 0.9 μM。形态分析、膜联蛋白 V 染色、半胱天冬酶活性检测以及 Bcl-2、Bax 和 Fas 的表达结果表明，川楝素的抗癌作用与其通过 p53-和 p53+肝癌细胞中线粒体依赖性途径诱导细胞凋亡有关。在体内实验中，BALB/c 小鼠皮下接种小鼠肝癌 H（22）细胞。腹腔内给予高剂量（0.69mg/kg）和低剂量（0.173mg/kg）川楝素均可强烈抑制肿瘤发生和凋亡反应。Bcl-2、Bax 和 Fas 的免疫组织化学结果表明，川楝素通过线粒体依赖性途径诱导细胞凋亡发挥抗癌作用，这与体外实验结果一致。上述结果表明，川楝素通过诱导肝癌细胞线粒体依赖性凋亡，在体内和体外均具有强烈的抗癌作用。
