α-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn) reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation.
α-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn) reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation.
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DOI：
10.1186/1741-7015-9-69
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发表时间：
2011-06-03
期刊：
影响因子：
9.3
通讯作者：
Otsuki Y
中科院分区：
文献类型：
--
作者：
Shibata MA;Iinuma M;Morimoto J;Kurose H;Akamatsu K;Okuno Y;Akao Y;Otsuki Y
山竹果在中国和阿育吠陀医学中具有悠久的药用历史。最近，从果实果皮中分离出来的化合物α-山竹素在体外研究中被证明可以诱导多种类型癌细胞的细胞死亡。这促使我们在具有 p53 突变的小鼠转移性乳腺癌的免疫活性异种移植模型中研究 α-山竹素的抗肿瘤生长和抗转移活性，该突变诱导与人类乳腺癌相似的转移谱。通过接种与转移性 BJMC3879luc2 细胞同系的 BALB/c 小鼠诱导乳腺肿瘤，随后使用微型渗透泵以 0、10 和 20 mg/kg/天的 α-山竹素处理并进行组织病理学检查。为了研究α-山竹素的抗肿瘤能力机制，还进行了体外研究。与对照组相比，20 mg/kg/天的 α-倒捻素组不仅体内存活率显着更高，而且肿瘤体积和淋巴结转移的复数均显着抑制。每天接受 20 mg/kg 剂量的小鼠乳腺肿瘤中的细胞凋亡水平显着增加，并且与活性 caspase-3 和 -9 表达的增加相关。在该剂量水平下注意到的其他显着效果是乳腺癌组织中微血管密度降低和含有管腔内肿瘤细胞的扩张淋巴管数量减少。在体外，α-山竹素诱导线粒体介导的细胞凋亡以及细胞周期中 G1 期停滞和 S 期抑制。由于 Akt 磷酸化的激活在多种致癌过程中发挥着核心作用，包括细胞增殖、抗凋亡细胞死亡、血管生成和转移，因此我们还研究了 α-山竹素处理在体外和体内诱导的 Akt 磷酸化的变化。定量分析和免疫组织化学表明，α-山竹素显着降低乳腺癌细胞培养物和体内乳腺癌组织中磷酸-Akt-苏氨酸 308 (Thr308) 的水平，但不降低丝氨酸 473 (Ser473) 的水平。由于淋巴结受累是乳腺癌患者最重要的预后因素，因此本研究中在携带 p53 突变的乳腺癌中检测到的 α-倒捻素的抗转移活性可能具有特定的临床应用。此外，α-山竹素可能具有化学预防功效和/或被证明可用作辅助治疗或作为治疗乳腺癌的补充替代药物。
The mangosteen fruit has a long history of medicinal use in Chinese and Ayurvedic medicine. Recently, the compound α-mangostin, which is isolated from the pericarp of the fruit, was shown to induce cell death in various types of cancer cells in in vitro studies. This led us to investigate the antitumor growth and antimetastatic activities of α-mangostin in an immunocompetent xenograft model of mouse metastatic mammary cancer having a p53 mutation that induces a metastatic spectrum similar to that seen in human breast cancers. Mammary tumors, induced by inoculation of BALB/c mice syngeneic with metastatic BJMC3879luc2 cells, were subsequently treated with α-mangostin at 0, 10 and 20 mg/kg/day using mini-osmotic pumps and histopathologically examined. To investigate the mechanisms of antitumor ability by α-mangostin, in vitro studies were also conducted. Not only were in vivo survival rates significantly higher in the 20 mg/kg/day α-mangostin group versus controls, but both tumor volume and the multiplicity of lymph node metastases were significantly suppressed. Apoptotic levels were significantly increased in the mammary tumors of mice receiving 20 mg/kg/day and were associated with increased expression of active caspase-3 and -9. Other significant effects noted at this dose level were decreased microvessel density and lower numbers of dilated lymphatic vessels containing intraluminal tumor cells in mammary carcinoma tissues. In vitro, α-mangostin induced mitochondria-mediated apoptosis and G1-phase arrest and S-phase suppression in the cell cycle. Since activation by Akt phosphorylation plays a central role in a variety of oncogenic processes, including cell proliferation, anti-apoptotic cell death, angiogenesis and metastasis, we also investigated alterations in Akt phosphorylation induced by α-mangostin treatment both in vitro and in vivo. Quantitative analysis and immunohistochemistry showed that α-mangostin significantly decreased the levels of phospho-Akt-threonine 308 (Thr308), but not serine 473 (Ser473), in both mammary carcinoma cell cultures and mammary carcinoma tissues in vivo. Since lymph node involvement is the most important prognostic factor in breast cancer patients, the antimetastatic activity of α-mangostin as detected in mammary cancers carrying a p53 mutation in the present study may have specific clinical applications. In addition, α-mangostin may have chemopreventive benefits and/or prove useful as an adjuvant therapy, or as a complementary alternative medicine in the treatment of breast cancer.
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影响因子：
5.4
作者：
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通讯作者：
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影响因子：
3.5
作者：
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Rapiti, E.
影响因子：
4.8
作者：
Fang, Jing;Ding, Min;Jiang, Bing-Hua
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Jiang, Bing-Hua