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Open AccessArticle

Rhein Induces Cell Death in HepaRG Cells through Cell Cycle Arrest and Apoptotic Pathway

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(4), 1060;
Received: 24 February 2018 / Revised: 25 March 2018 / Accepted: 31 March 2018 / Published: 2 April 2018
(This article belongs to the Special Issue Frontiers in Drug Toxicity Prediction)
Rhein, a naturally occurring active anthraquinone found abundantly in various medicinal and nutritional herbs, possesses a wide spectrum of pharmacological effects. Furthermore, previous studies have reported that rhein could induce hepatotoxicity in rats. However, its cytotoxicity and potential molecular mechanisms remain unclear. Therefore, the present study aimed to investigate the cytotoxicity of rhein on HepaRG cells and the underlying mechanisms of its cytotoxicity. Our results demonstrate, by 3-(4,5-dimethyl thiazol-2-yl-)-2,5-diphenyl tetrazolium bromide (MTT) and Annexin V-fluoresce isothiocyanate (FITC)/propidium iodide (PI) double-staining assays, that rhein significantly inhibited cell viability and induced apoptosis in HepaRG cells. Moreover, rhein treatment resulted in the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and S phase cell cycle arrest. The results of Western blotting showed that rhein treatment resulted in a significant increase in the protein levels of Fas, p53, p21, Bax, cleaved caspases-3, -8, -9, and poly(ADP-ribose)polymerase (PARP). The protein expression of Bcl-2, cyclin A, and cyclin-dependent kinase 2 (CDK 2) was decreased. In conclusion, these results suggest that rhein treatment could inhibit cell viability of HepaRG cells and induce cell death through cell cycle arrest in the S phase and activation of Fas- and mitochondrial-mediated pathways of apoptosis. These findings emphasize the need to assess the risk of exposure for humans to rhein. View Full-Text
Keywords: rhein; hepatotoxicity; HepaRG cells; ROS; apoptosis rhein; hepatotoxicity; HepaRG cells; ROS; apoptosis
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You, L.; Dong, X.; Yin, X.; Yang, C.; Leng, X.; Wang, W.; Ni, J. Rhein Induces Cell Death in HepaRG Cells through Cell Cycle Arrest and Apoptotic Pathway. Int. J. Mol. Sci. 2018, 19, 1060.

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