首页> 外文期刊>Molecules >The (+)-Brevipolide H Displays Anticancer Activity against Human Castration-Resistant Prostate Cancer The Role of Oxidative Stress and Akt/mTOR/p70S6K-Dependent Pathways in G1 Checkpoint Arrest and Apoptosis
【24h】

The (+)-Brevipolide H Displays Anticancer Activity against Human Castration-Resistant Prostate Cancer The Role of Oxidative Stress and Akt/mTOR/p70S6K-Dependent Pathways in G1 Checkpoint Arrest and Apoptosis

机译:(+) - Brevipolide H显示抗癌抗癌前列腺癌的抗癌活动,氧化应激和AKT / MTOR / P70S6K依赖性途径在G1检查点停滞和凋亡中的作用

获取原文
获取外文期刊封面目录资料

摘要

Because conventional chemotherapy is not sufficiently effective against prostate cancer, various examinations have been performed to identify anticancer activity of naturally occurring components and their mechanisms of action. The (+)-brevipolide H, an α-pyrone-based natural compound, induced potent and long-term anticancer effects in human castration-resistant prostate cancer (CRPC) PC-3 cells. Flow cytofluorometric analysis with propidium iodide staining showed (+)-brevipolide H-induced G1 arrest of cell cycle and subsequent apoptosis through induction of caspase cascades. Since Akt/mTOR pathway has been well substantiated in participating in cell cycle progression in G1 phase, its signaling and downstream regulators were examined. Consequently, (+)-brevipolide H inhibited the signaling pathway of Akt/mTOR/p70S6K. The c-Myc inhibition and downregulation of G1 phase cyclins were also attributed to (+)-brevipolide H action. Overexpression of myristoylated Akt significantly rescued mTOR/p70S6K and downstream signaling under (+)-brevipolide H treatment. ROS and Ca2+, two key mediators in regulating intracellular signaling, were determined, showing that (+)-brevipolide H interactively induced ROS production and an increase of intracellular Ca2+ levels. The (+)-Brevipolide H also induced the downregulation of anti-apoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xL) and loss of mitochondrial membrane potential, indicating the contribution of mitochondrial dysfunction to apoptosis. In conclusion, the data suggest that (+)-brevipolide H displays anticancer activity through crosstalk between ROS production and intracellular Ca2+ mobilization. In addition, suppression of Akt/mTOR/p70S6K pathway associated with downregulation of G1 phase cyclins contributes to (+)-brevipolide H-mediated anticancer activity, which ultimately causes mitochondrial dysfunction and cell apoptosis. The data also support the biological significance and, possibly, clinically important development of natural product-based anticancer approaches.
机译:由于常规化疗对前列腺癌不够有效,因此已经进行了各种检查以确定天然存在的组分及其作用机制的抗癌活性。 (+) - Brevipolide H,基于α-吡喃酮的天然化合物,诱导有效和长期抗癌效应在人阉割的前列腺癌(CRPC)PC-3细胞中。流动性细胞杂氟量分析与碘化丙锭染色显示(+) - Brevipolide H诱导的细胞周期G1遗留和随后通过肠脑级联诱导凋亡。由于AKT / MTOR途径在参与G1相中的细胞周期进展方面很好地证实,因此检查其信号传导和下游调节器。因此,(+) - Brevipolide H抑制AKT / MTOR / P70S6K的信号通路。 G1相环素的C-MYC抑制和下调也归因于(+) - Brevipolide H动作。 MyRISTOODALATED AKT的过度表达显着救出了(+) - Brevipolide H处理下的MTOR / P70S6K和下游信号。 ROS和CA2 +,确定调节细胞内信号传导的两个关键介质,显示(+) - Brevipolide H以交互式诱导ROS产生和细胞内Ca2 +水平的增加。 (+) - Brevipolide H还诱导了抗凋亡Bcl-2家族蛋白(Bcl-2和Bcl-x1)的下调,并且对线粒体膜电位的丧失,表明线粒体功能障碍对细胞凋亡的贡献。总之,数据表明(+) - Brevipolide H通过ROS生产和细胞内CA2 +动员的串扰显示抗癌活动。此外,与G1相周期环素的下调相关的AKT / mTOR / P70S6K途径有助于(+) - Brevipolide H介导的抗癌活性,最终导致线粒体功能障碍和细胞凋亡。数据还支持基于天然产品的抗癌方法的生物学意义,并且可能,临床上重要性发展。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号