RESUMO
Aloe-emodin (1,8-dihydroxy-3-hydroxymethyl-anthraquinone), derived from some Chinese edible medicinal herbs, exerts a potential anticancer activity on various cancer cells, making it a drug candidate for cancer therapy. Yet, the role of aloe-emodin in pyroptosis, a new type of cell death, is uncharacterized. In this study, we explored the molecular mechanisms of aloe-emodin-triggered pyroptosis. Aloe-emodin inhibited proliferation and migration and triggered caspase-dependent cell death of HeLa cells in a dose-dependent manner. Aloe-emodin caused mitochondrial dysfunction and induced pyroptosis by activating the caspase-9/3/GSDME axis. Transcriptional analysis showed extensive changes in gene expressions in cellular pathways, including MAPK, p53, and PI3K-Akt pathways when treated with aloe-emodin. This study not only identified a novel role of aloe-emodin in pyroptotic cell death, but also performed a systematical genome-wide analysis of cellular pathways responding to aloe-emodin, providing a theoretical basis for applying anthraquinone derivatives in the treatment of GSDME-expressing cancers.
RESUMO
BACKGROUND: Sonchus oleraceus is a large and widespread plant in the world. It is edible to humans as a leaf vegetable and is also used as a folklore medicinal herb in the treatment of infections and inflammatory disease, but limited research on its chemical constituents has been done. OBJECTIVE: To isolate and identify the bioactive ingredients from S. oleraceus. METHODS: 20kg of S. oleraceus was extracted twice with 75% alcohol. The concentrated extract was suspended in H2O and partitioned with petroleum ether, dichloromethane, ethyl acetate and n-butanol, respectively. The ethyl acetate phase was subjected to repeated normal chromatography on a silica gel column chromatography and eluted with a gradient of CH2Cl2-MeOH to give 12 crude fractions. Fraction 6 was subjected to ODS silica gel column chromatography, Sephadex LH-20 and HPLC to yield 1 and 2. Cell viability of 1 and 2 on A549, H292 and Caco2 cell lines were assayed by MTT method. Apoptosis analysis and apoptosis related proteins were detected subsequently. RESULTS: Two new sesquiterpenes were isolated from S. oleraceus and identified by NMR spectra and HR-ESIMS. 1 selectively suppressed the viability of A549 and H292 cells with IC50 values of 14.2, and 19.5µM respectively, while possessing no cytotoxicity against Caco2 cells (IC50 > 100µM). 2 did not exhibit cytotoxicity against A549, H292 and Caco2 cells (IC50 > 100µM). 1 significantly decreased the density of live cells and could cause cell apoptosis at 10 and 20µM in a dose-dependent manner. After treatment of 1 for 24h, the level of cleaved caspase-3 was increased accompanied by the reduction in procaspase-3 expression, and the downregulation of Bcl-2 was associated with the enhancement of Bax expression. 1 could lead to the up-regulation of cytochrome c and activation of caspase-9. CONCLUSION: 1 and 2 are new sesquiterpenes from S. oleraceus. 1 could induce apoptosis in A549 and H292 cells through Bax/caspase-9 pathway.