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

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

研究成果: 雜誌貢獻文章同行評審

42 引文 斯高帕斯(Scopus)

摘要

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 μM. 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-3β, and NF-κB. 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.
原文英語
頁(從 - 到)238-245
頁數8
期刊Chemical Research in Toxicology
24
發行號2
DOIs
出版狀態已發佈 - 二月 18 2011

ASJC Scopus subject areas

  • Toxicology

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