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Condensed tannins from Ulmus pumila L. leaves induce G2/M phase arrest and apoptosis via caspase-cascade activation in TFK-1 cholangiocarcinoma cells.

Condensed tannins the polyphenolic compounds that are widespread in plants have been proved to have antitumor potential. Here, we purified the bioactive condensed tannins from leaves of Ulmus pumila L. and explored their structural characteristics, antitumor effect on TFK-1 cholangiocarcinoma cells as well as the related potential mechanism. The UV-Vis, FT-IR spectroscopy, ESI-Full-MS, and thiolysis-HPLC-ESI-MS demonstrated that U. pumila condensed tannins (UCTs) consisted essentially of procyanidins with epicatechin as the main flavan-3-ol extension unit. The UCTs could significantly reduce the survival rate of human cholangiocarcinoma TFK-1, SK-CHA-1, and MZ-CHA-1 cells with the better inhibitory effect on TFK-1 cell proliferation. Flow cytometric assay showed that UCTs affected TFK-1 survival by G2/M phase arrest and inducing apoptosis in a dose-dependent manner. In addition, a total of 6592 differentially expressed genes (DEGs), consisting of 94 upregulated and 6498 downregulated DEGs, were identified between untreated and UCTs-treated TFK-1 cells using RNA-seq technology. Enrichment analysis based on the KEGG database revealed that these DEGs were closely associated with cell cycle and p53 apoptotic signaling pathways. Furthermore, qRT-PCR confirmed that treatment of UCTs to TFK-1 cells caused significant changes in the expression of cyclin E, cdc25 A, cytochrome c, caspase-3, and caspase-8. These results indicated that UCTs exhibited the growth inhibition effect on TFK-1 cells possibly via G2/M cell cycle arrest and activation of caspase-cascade to induce apoptosis, and had potential as an anti-cholangiocarcinoma drug for further development. PRACTICAL APPLICATIONS: Ulmus pumila L. as a valuable tree species has been widely used in fields of medicine and food. Condensed tannins, the polyphenolic compounds widespread in plants, have been proved to have antitumor potential and be safe to normal cells. In this study, the condensed tannins from leaves of U. pumila (UCTs) remarkably suppressed cholangiocarcinoma (CCA) cell viability possibly via G2/M cell cycle arrest and activation of caspase-cascade to induce apoptosis. The results provided evidence for the application of UCTs as a potential therapeutic drug for CCA tumor.