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A Novel Flavonoid Kushenol Z from Sophora flavescens Mediates mTOR Pathway by Inhibiting Phosphodiesterase and Akt Activity to Induce Apoptosis in Non-Small-Cell Lung Cancer Cells

The roots of Sophora flavescens (SF) are clinically used as a traditional Chinese medicine for the treatment of various lung diseases. In this study, we investigated the mechanism by which SF inhibits proliferation and induces apoptosis in non-small-cell lung cancer (NSCLC) cells. A new compound, ku...

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Autores principales: Chen, Hao, Yang, Jie, Hao, Ji, Lv, Yibing, Chen, Lu, Lin, Qinxiong, Yuan, Jingquan, Yang, Xinzhou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943755/
https://www.ncbi.nlm.nih.gov/pubmed/31817093
http://dx.doi.org/10.3390/molecules24244425
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author Chen, Hao
Yang, Jie
Hao, Ji
Lv, Yibing
Chen, Lu
Lin, Qinxiong
Yuan, Jingquan
Yang, Xinzhou
author_facet Chen, Hao
Yang, Jie
Hao, Ji
Lv, Yibing
Chen, Lu
Lin, Qinxiong
Yuan, Jingquan
Yang, Xinzhou
author_sort Chen, Hao
collection PubMed
description The roots of Sophora flavescens (SF) are clinically used as a traditional Chinese medicine for the treatment of various lung diseases. In this study, we investigated the mechanism by which SF inhibits proliferation and induces apoptosis in non-small-cell lung cancer (NSCLC) cells. A new compound, kushenol Z (KZ), and 14 known flavonoids were isolated from SF. KZ, sophoraflavanone G, and kushenol A demonstrated potent cytotoxicity against NSCLC cells in a dose- and time-dependent manner; KZ showed a wide therapeutic window. We also found that KZ induced NSCLC cell apoptosis by increasing the Bax/Bcl-2 ratio and by activating caspase-3 and caspase-9 leading to mitochondrial apoptosis, and upregulated CHOP and activatedcaspase-7 and caspase-12, which triggered the endoplasmic reticulum stress pathway. After KZ treatment, we observed cAMP accumulation, which reflected the inhibition of cAMP-phosphodiesterase (PDE), along with the increase in PKA activity; additionally, phospho-p70 S6 kinase was downregulated. KZ also attenuated the phosphorylation of Akt and PRAS40, which was partially rescued by an Akt activator. This suggested that KZ mediated the antiproliferative activity in NSCLC cells by inhibiting the mTOR pathway through the inhibition of cAMP-PDE and Akt. These findings suggested that KZ may be used as a promising cAMP-PDE and Akt inhibitor in targeted chemotherapeutic drug development.
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spelling pubmed-69437552020-01-10 A Novel Flavonoid Kushenol Z from Sophora flavescens Mediates mTOR Pathway by Inhibiting Phosphodiesterase and Akt Activity to Induce Apoptosis in Non-Small-Cell Lung Cancer Cells Chen, Hao Yang, Jie Hao, Ji Lv, Yibing Chen, Lu Lin, Qinxiong Yuan, Jingquan Yang, Xinzhou Molecules Article The roots of Sophora flavescens (SF) are clinically used as a traditional Chinese medicine for the treatment of various lung diseases. In this study, we investigated the mechanism by which SF inhibits proliferation and induces apoptosis in non-small-cell lung cancer (NSCLC) cells. A new compound, kushenol Z (KZ), and 14 known flavonoids were isolated from SF. KZ, sophoraflavanone G, and kushenol A demonstrated potent cytotoxicity against NSCLC cells in a dose- and time-dependent manner; KZ showed a wide therapeutic window. We also found that KZ induced NSCLC cell apoptosis by increasing the Bax/Bcl-2 ratio and by activating caspase-3 and caspase-9 leading to mitochondrial apoptosis, and upregulated CHOP and activatedcaspase-7 and caspase-12, which triggered the endoplasmic reticulum stress pathway. After KZ treatment, we observed cAMP accumulation, which reflected the inhibition of cAMP-phosphodiesterase (PDE), along with the increase in PKA activity; additionally, phospho-p70 S6 kinase was downregulated. KZ also attenuated the phosphorylation of Akt and PRAS40, which was partially rescued by an Akt activator. This suggested that KZ mediated the antiproliferative activity in NSCLC cells by inhibiting the mTOR pathway through the inhibition of cAMP-PDE and Akt. These findings suggested that KZ may be used as a promising cAMP-PDE and Akt inhibitor in targeted chemotherapeutic drug development. MDPI 2019-12-04 /pmc/articles/PMC6943755/ /pubmed/31817093 http://dx.doi.org/10.3390/molecules24244425 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Hao
Yang, Jie
Hao, Ji
Lv, Yibing
Chen, Lu
Lin, Qinxiong
Yuan, Jingquan
Yang, Xinzhou
A Novel Flavonoid Kushenol Z from Sophora flavescens Mediates mTOR Pathway by Inhibiting Phosphodiesterase and Akt Activity to Induce Apoptosis in Non-Small-Cell Lung Cancer Cells
title A Novel Flavonoid Kushenol Z from Sophora flavescens Mediates mTOR Pathway by Inhibiting Phosphodiesterase and Akt Activity to Induce Apoptosis in Non-Small-Cell Lung Cancer Cells
title_full A Novel Flavonoid Kushenol Z from Sophora flavescens Mediates mTOR Pathway by Inhibiting Phosphodiesterase and Akt Activity to Induce Apoptosis in Non-Small-Cell Lung Cancer Cells
title_fullStr A Novel Flavonoid Kushenol Z from Sophora flavescens Mediates mTOR Pathway by Inhibiting Phosphodiesterase and Akt Activity to Induce Apoptosis in Non-Small-Cell Lung Cancer Cells
title_full_unstemmed A Novel Flavonoid Kushenol Z from Sophora flavescens Mediates mTOR Pathway by Inhibiting Phosphodiesterase and Akt Activity to Induce Apoptosis in Non-Small-Cell Lung Cancer Cells
title_short A Novel Flavonoid Kushenol Z from Sophora flavescens Mediates mTOR Pathway by Inhibiting Phosphodiesterase and Akt Activity to Induce Apoptosis in Non-Small-Cell Lung Cancer Cells
title_sort novel flavonoid kushenol z from sophora flavescens mediates mtor pathway by inhibiting phosphodiesterase and akt activity to induce apoptosis in non-small-cell lung cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943755/
https://www.ncbi.nlm.nih.gov/pubmed/31817093
http://dx.doi.org/10.3390/molecules24244425
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