https://scholars.lib.ntu.edu.tw/handle/123456789/564749
標題: | 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 | 作者: | Sheng Y.-H. Leu W.-J. Chen C.-N. Hsu J.-L. Liu Y.-T. LIH-CHING HSU Hou D.-R. JIH-HWA GUH |
公開日期: | 2020 | 卷: | 25 | 期: | 12 | 起(迄)頁: | 25122929 | 來源出版物: | Molecules | 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. ? 2020 by the authors. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85087514328&doi=10.3390%2fmolecules25122929&partnerID=40&md5=d2f8a37051fc24a6502be4053023ee25 https://scholars.lib.ntu.edu.tw/handle/123456789/564749 |
ISSN: | 14203049 | DOI: | 10.3390/molecules25122929 | SDG/關鍵字: | antineoplastic agent; brevipolide H; cyclopropane derivative; MTOR protein, human; protein kinase B; pyrone derivative; S6 kinase; target of rapamycin kinase; tumor marker; apoptosis; castration resistant prostate cancer; cell proliferation; drug effect; G1 phase cell cycle checkpoint; gene expression regulation; genetics; human; male; metabolism; mitochondrial membrane potential; oxidative stress; pathology; signal transduction; tumor cell culture; Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Cyclopropanes; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; Male; Membrane Potential, Mitochondrial; Oxidative Stress; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; Pyrones; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Cells, Cultured |
顯示於: | 藥學系 |
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