Abstract
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.
Highlights
Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid) is an anthraquinone compound and is primarily separated from Cassia occidentalis, Polygonum multiflorum, and Rheum palmatum L., which have been widely used as a laxative or a stomachic agent in many countries for a long time [1,2]
The experimental results show that rhein treatment resulted in a dose-dependent increase in Lactate dehydrogenase (LDH) leakage from HepaRG cells
Previous studies have suggested that rhein might be one of the major hepatotoxic and nephrotoxic ingredients in Rheum palmatum L. [33]
Summary
Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid) (see Figure 1) is an anthraquinone compound and is primarily separated from Cassia occidentalis, Polygonum multiflorum, and Rheum palmatum L., which have been widely used as a laxative or a stomachic agent in many countries for a long time [1,2]. Modern pharmacological studies have suggested that rhein possesses a number of biological properties including anticancer [3], antiviral [4], anti-inflammatory [5], and antimycobacterial effects [6]. Previous studies have shown that rhein inhibits the growth of various cells such as human tongue cancer cells (SCC-4), human lung cancer cells (A-549), human nasopharyngeal carcinoma cells (NPC), and human promyelocytic leukemia cells (HL-60) [2,7,8,9]. Rhein has been reported to be involved in a series of mitochondrial functions including oxidative phosphorylation and inhibits oxidation of FAD- or NAD-linked substrates. It mediates toxicity in rat primary hepatocytes through the generation of reactive oxygen species [16,17]
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