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

36 引文 (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

指紋

Antrodia
Breast Neoplasms
Molecules
Apoptosis
Glycogen Synthase Kinase 3
Apoptosis Regulatory Proteins
Phosphorylation
Poly(ADP-ribose) Polymerases
Cell growth
Cytochromes c
antrocin
Phosphatidylinositol 3-Kinases
Caspase 3
Doxorubicin
Small Interfering RNA
Cisplatin
Inhibitory Concentration 50
Down-Regulation
Clinical Trials
Messenger RNA

ASJC Scopus subject areas

  • Toxicology

引用此文

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title = "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",
abstract = "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.",
author = "Rao, {Yerra Koteswara} and Wu, {Alexander T H} and Madamanchi Geethangili and Huang, {Ming Te} and Chao, {Wan Ju} and Wu, {Chih Hsiung} and Deng, {Win Ping} and Chi-Tai Yeh and Tzeng, {Yew Min}",
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T1 - 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

AU - Rao, Yerra Koteswara

AU - Wu, Alexander T H

AU - Geethangili, Madamanchi

AU - Huang, Ming Te

AU - Chao, Wan Ju

AU - Wu, Chih Hsiung

AU - Deng, Win Ping

AU - Yeh, Chi-Tai

AU - Tzeng, Yew Min

PY - 2011/2/18

Y1 - 2011/2/18

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AB - 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.

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