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Molecules 2016, 21(6), 813; doi:10.3390/molecules21060813

An Ingenol Derived from Euphorbia kansui Induces Hepatocyte Cytotoxicity by Triggering G0/G1 Cell Cycle Arrest and Regulating the Mitochondrial Apoptosis Pathway in Vitro

1
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China
2
Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine, Changzhou 213003, China
*
Authors to whom correspondence should be addressed.
Academic Editors: Quan-Bin Han and Jian-Xin Pu
Received: 5 May 2016 / Revised: 16 June 2016 / Accepted: 17 June 2016 / Published: 22 June 2016
(This article belongs to the Special Issue Diterpene and Its Significance in Natural Medicine)
View Full-Text   |   Download PDF [8974 KB, uploaded 22 June 2016]   |  

Abstract

Natural product lingenol, a purified diterpenoid compound derived from the root of Euphorbia kansui, exerts serious hepatotoxicity; however, the molecular mechanisms remain to be defined. In the present study, cell counting Kit-8 (CCK-8), inverted phase contrast microscope and flow cytometry were used to demonstrate that lingenol significantly inhibited L-O2 cells proliferation, and induced cell cycle arrest and apoptosis. Moreover, the results investigated that lingenol markedly disrupted mitochondrial functions by high content screening (HCS). In addition, the up-regulation of cytochrome c, AIF and Apaf-1 and activation of caspases were found in L-O2 cells detected by Western blotting and ELISA assay, which was required for lingenol activation of cytochrome c-mediated caspase cascades and AIF-mediated DNA damage. Mechanistic investigations revealed that lingenol significantly down-regulated the Bcl-2/Bax ratio and enhanced the reactive oxygen species (ROS) in L-O2 cells. These data collectively indicated that lingenol modulation of ROS and Bcl-2/Bax ratio led to cell cycle arrest and mitochondrial-mediated apoptosis in L-O2 cells in vitro. All of these results will be helpful to reveal the hepatotoxicity mechanism of Euphorbia kansui and to effectively guide safer and better clinical application of this herb. View Full-Text
Keywords: lingenol; hepatotoxicity; cell cycle arrest; cell apoptosis; high content screen; ROS; Bcl-2/Bax lingenol; hepatotoxicity; cell cycle arrest; cell apoptosis; high content screen; ROS; Bcl-2/Bax
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Yan, X.; Zhang, L.; Cao, Y.; Yao, W.; Tang, Y.; Ding, A. An Ingenol Derived from Euphorbia kansui Induces Hepatocyte Cytotoxicity by Triggering G0/G1 Cell Cycle Arrest and Regulating the Mitochondrial Apoptosis Pathway in Vitro. Molecules 2016, 21, 813.

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