Identification of Antrocin from Antrodia camphorata as a Selective and Novel Class of Small Molecule Inhibitor of Akt/mTOR Signaling in Metastatic Breast Cancer MDA-MB-231 Cells

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• 作者：Yerra Koteswara Rao ; Alexander T. H. Wu ; Madamanchi Geethangili ; Ming-Te Huang ; Wan-Ju Chao ; Chih-Hsiung Wu ; Win-Ping Deng ; Chi-Tai Yeh ; Yew-Min Tzeng
• 刊名：Chemical Research in Toxicology
• 出版年：2011
• 出版时间：February 18, 2011
• 年：2011
• 卷：24
• 期：2
• 页码：238-245
• 全文大小：1096K
• 年卷期：v.24,no.2(February 18, 2011)
• ISSN：1520-5010

文摘

The PI3K/Akt/mTOR pathway is considered to be an attractive target for the development of novel anticancer molecules. This paper reports for the first time that a small molecule, antrocin (MW = 234), from Antrodia camphorata was a potent antagonist in various cancer types, being highest in metastatic breast cancer MDA-MB-231 cells (MMCs) with an IC₅₀ value of 0.6 渭M. Antrocin was a superior antiproliferator in MMCs as compared with doxorubicin and cisplatin, prevents colony formation, and was nontoxic to nontumorgenic MCF10A and HS-68 cells. Antrocin induced dose-dependent apoptosis in MMCs and caused cleavage of caspase-3 and poly(ADP-ribose) polymerase. Antrocin also caused a time-dependent decrease in protein expression of anti-apoptotic Bcl-2, Bcl-xL, survivin, and their mRNA, with concomitant increase in pro-apoptotic Bax and cytosolic cytochrome c. In a mechanistic study, antrocin suppressed the phosphorylation of Akt and its downstream effectors mTOR, GSK-3尾, and NF-魏B. Furthermore, down-regulation of Akt by small interfering RNA prior to antrocin treatment resulted in enhanced cell growth inhibition and apoptosis. Thus, antrocin as an Akt/mTOR dual inhibitor has broad applicability in the development of a clinical trial candidate for the treatment of metastatic breast cancer.