Antitumor Activity of Vanicoside B Isolated from Persicaria dissitiflora by Targeting CDK8 in Triple-Negative Breast Cancer Cells.

A flavonoid glycoside, quercitrin (1), and two phenylpropanoyl sucrose derivatives, vanicoside B (2) and lapathoside C (3), were isolated for the first time from the herb Persicaria dissitiflora. Vanicoside B (2) exhibited antiproliferative activity against a panel of cancer cell lines in triple-negative breast cancer (TNBC) MDA-MB-231 cells. The underlying mechanisms of the antitumor activity of 2 were investigated in TNBC cells. Upregulation of cyclin-dependent kinase 8 (CDK8) was observed in a claudin-low molecular subtype of TNBC cells. A molecular modeling study indicated that 2 showed a high affinity for CDK8. Further investigations revealed that 2 suppressed CDK8-mediated signaling pathways and the expression of epithelial-mesenchymal transition proteins and induced cell cycle arrest and apoptosis in MDA-MB-231 and HCC38 TNBC cells. Moreover, 2 inhibited tumor growth without overt toxicity in a nude mouse xenograft model implanted with MDA-MB-231 cells. Taken together, these findings demonstrate the significance of CDK8 activity in TNBC and suggest a potential use of 2 as a therapeutic candidate for the treatment of aggressive human triple-negative breast cancer.

Silibinin suppresses growth of human colorectal carcinoma SW480 cells in culture and xenograft through down-regulation of beta-catenin-dependent signaling.

Mutations in APC/beta-catenin resulting in an aberrant activation of Wnt/beta-catenin pathway are common in colorectal cancer (CRC), suggesting that targeting the beta-catenin pathway with chemopreventive/anticancer agents could be a potential translational approach to control CRC. Using human CRC cell lines harboring mutant (SW480) versus wildtype (HCT116) APC gene and alteration in beta-catenin pathway, herein we performed both in vitro and in vivo studies to examine for the first time whether silibinin targets beta-catenin pathway in its efficacy against CRC. Silibinin treatment inhibited cell growth, induced cell death, and decreased nuclear and cytoplasmic levels of beta-catenin in SW480 but not in HCT116 cells, suggesting its selective effect on the beta-catenin pathway and associated biologic responses. Other studies, therefore, were performed only in SW480 cells where silibinin significantly decreased beta-catenin-dependent T-cell factor-4 (TCF-4) transcriptional activity and protein expression of beta-catenin target genes such as c-Myc and cyclin D1. Silibinin also decreased cyclin-dependent kinase 8 (CDK8), a CRC oncoprotein that positively regulates beta-catenin activity, and cyclin C expression. In a SW480 tumor xenograft study, 100- and 200-mg/kg doses of silibinin feeding for 6 weeks inhibited tumor growth by 26% to 46% (P < .001). Analyses of xenografts showed that similar to cell culture findings, silibinin decreases proliferation and expression of beta-catenin, cyclin D1, c-Myc, and CDK8 but induces apoptosis in vivo. Together, these findings suggest that silibinin inhibits the growth of SW480 tumors carrying the mutant APC gene by down-regulating CDK8 and beta-catenin signaling and, therefore, could be an effective agent against CRC.