Characterized mechanism of α-mangostin-induced cell death:: Caspase-independent apoptosis with release of endonuclease-G from mitochondria and increased miR-143 expression in human colorectal cancer DLD-1 cells
Characterized mechanism of α-mangostin-induced cell death:: Caspase-independent apoptosis with release of endonuclease-G from mitochondria and increased miR-143 expression in human colorectal cancer DLD-1 cells
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DOI：
10.1016/j.bmc.2007.04.071
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发表时间：
2007-08-15
影响因子：
3.5
通讯作者：
Akao, Yukihiro
中科院分区：
文献类型：
--
作者：
Nakagawa, Yoshihito;Iinuma, Munekazu;Akao, Yukihiro
α -山竹苷是山竹果皮中的一种山酮，对人结肠癌DLD-1细胞的体外细胞毒性进行了评价。在20 μ M以上，α -山竹苷处理后，活细胞数量持续下降。形态学结果表明，20 μ M α -山竹苷的细胞毒作用主要是由于细胞凋亡引起的。Western blotting，使用caspase抑制剂进行细胞凋亡抑制试验的结果，以及caspase活性检查均未显示任何被测试的caspase激活。然而，线粒体释放的内切酶- g随线粒体膜电位的降低而减少。phospho-Erk1/2在治疗开始后的早期升高，随后下降，在治疗后期再次升高。另一方面，在处理6it后，磷酸化akt水平随着细胞凋亡的过程而急剧降低。有趣的是，在翻译中负调控Erk5的microRNA- 143的水平在治疗开始后逐渐升高，直到24小时。我们还研究了a-山竹苷和5-FU联合治疗DLD-1细胞对DLD-1细胞生长的协同抑制作用，5-FU是治疗结直肠癌最有效的化疗药物之一。与α -山竹苷5 μ M或α -山竹苷5 μ M - fu单独处理相比，α -山竹苷和5- fu共处理2.5 μ M时，生长抑制增强。这些发现提示了α -山竹苷诱导细胞凋亡的独特机制及其作为一种有效的化学增敏剂的作用。(C) 2007 Elsevier Ltd.版权所有。
alpha-Mangostin, a xanthone from the pericarps of mangosteen (Garcinia mangostana Linn.), was evaluated for in vitro cytotoxicity against human colon cancer DLD-1 cells. The number of viable cells was consistently decreased by the treatment with a-mangostin at more than 20 mu M. The cytotoxic effect of 20 mu M alpha-mangostin was found to be mainly due to apoptosis, as indicated by morphological findings. Western blotting, the results of an apoptosis inhibition assay using caspase inhibitors, and the examination of caspase activity did not demonstrate the activation of any of the caspases tested. However, endonuclease-G released from mitochondria with the decreased mitochondrial membrane potential was shown. The levels of phospho-Erk1/2 were increased in the early phase until I h after the start of treatment and thereafter decreased, and increased again in the late phase. On the other hand, the level of phospho-Akt was sharply reduced with the process of apoptosis after 6 It of treatment. Interestingly, the level of microRNA- 143, which negatively regulates Erk5 at translation, gradually increased until 24 It following the start of treatment. We also examined the synergistic growth suppression in DLD-1 cells by the combined treatment of the cells with a-mangostin and 5-FU which is one of the most effective chemotherapeutic agents for colorectal adenocarcinoma. The co-treatment with alpha-mangostin and 5-FU, both at 2.5 mu M, augmented growth inhibition compared with the treatment with 5 VM of a-mangostin or 5 mu M 5-FU alone. These findings indicate unique mechanisms of alpha-mangostin- induced apoptosis and its action as an effective chemosensitizer. (C) 2007 Elsevier Ltd. All rights reserved.