Sheng Y.-H.Leu W.-J.Chen C.-N.Hsu J.-L.Liu Y.-T.LIH-CHING HSUHou D.-R.JIH-HWA GUH2021-06-022021-06-02202014203049https://www.scopus.com/inward/record.uri?eid=2-s2.0-85087514328&doi=10.3390%2fmolecules25122929&partnerID=40&md5=d2f8a37051fc24a6502be4053023ee25https://scholars.lib.ntu.edu.tw/handle/123456789/564749Because 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.[SDGs]SDG3antineoplastic 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, Culturedjournal article10.3390/molecules25122929326305322-s2.0-85087514328