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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

1
Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning 530001, China
2
School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China
3
College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
4
Guangxi Institute of Medicinal Plant, Nanning 530023, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Jóhannes Reynisson FRSC
Molecules 2019, 24(24), 4425; https://doi.org/10.3390/molecules24244425
Received: 31 October 2019 / Revised: 26 November 2019 / Accepted: 27 November 2019 / Published: 4 December 2019
(This article belongs to the Special Issue Advances in Anticancer Drug Discovery)
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. View Full-Text
Keywords: Kushenol Z; NSCLC; apoptosis; cAMP; Akt; mTOR Kushenol Z; NSCLC; apoptosis; cAMP; Akt; mTOR
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Chen, H.; Yang, J.; Hao, J.; Lv, Y.; Chen, L.; Lin, Q.; Yuan, J.; Yang, X. 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. Molecules 2019, 24, 4425.

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