wogonoside and Breast-Neoplasms

Twist1 is involved in tumor initiation and progression, which especially contributes to tumor invasion and metastasis. Wogonoside is the main in-vivo metabolite of wogonin, and it is also a natural product with potential treatment effects against cancer.. In this study, we investigated the in-vitro anti-invasion and in-vivo anti-metastasis effects of wogonoside on breast cancer cells and uncovered its underlying mechanism.. The results showed that wogonoside could suppress the growth and metastasis of breast tumor in the orthotopic model of MDA-MB-231 cells. We found that wogonoside could reduce the overexpression of TNF-α, TRAF2 and TRAF4 in later stage of tumor, and improved tumor microenvironment. Therefore, TNF-α was utilized to induce metastases of breast cancer cell in vitro. Wogonoside could inhibit invasion and migration in TNF-α-induced MDA-MB-231, MDA-MB-435, and BT-474 cells. Mechanically, wogonoside inactivated NF-κB signaling through decreasing the protein expression of TRAF2/4, which further inhibited Twist1 expression. Consequently, wogonoside could down-regulate MMP-9, MMP-2, vimentin and CD44v6 expression in TNF-α-induced MDA-MB-231 and MDA-MB-435 cells. Then, these findings were proved in TNF-α + TGF-β1-induced MCF7 cells.. Wogonoside might be a potential therapeutic agent for the treatment of tumor metastasis in breast cancer.

Topics: Animals; Breast Neoplasms; Cell Movement; Female; Flavanones; Glucosides; Humans; Mice; Mice, Nude; Neoplasm Invasiveness; TNF Receptor-Associated Factor 2; TNF Receptor-Associated Factor 4; Transfection; Tumor Necrosis Factor-alpha

Wogonoside, a main flavonoid component derived from the root of Scutellaria baicalensis Georgi, has been reported to have anti-angiogenesis and anti-leukemia activities. However, whether it can inhibit tumor angiogenesis is unclear. In this study, we investigate the inhibitory effect of wogonoside on angiogenesis in breast cancer and its underlying mechanisms. ELISA assay shows that wogonoside (25, 50, and 100 µM) decreases the secretion of VEGF in MCF-7 cells by 30.0%, 35.4%, and 40.1%, respectively. We find it inhibits angiogenesis induced by the conditioned media from MCF-7 cells in vitro and in vivo by migration, tube formation, rat aortic ring, and chicken chorioallantoic membrane (CAM) assay. Meanwhile, wogonoside can inhibit the growth and angiogenesis of MCF-7 cells xenografts in nude mice. The reduction of tumor weight can be found both in wogonoside (80 mg/kg) and bevacizumab (20 mg/kg) treated group, and the tumor inhibition rate is 42.1% and 48.7%, respectively. In addition, mechanistic studies demonstrate that wogonoside suppresses the activation of Wnt/β-catenin pathway in MCF-7 cells. Wogonoside (100 µM) decreases the intracellular level of Wnt3a, increases the expression of GSK-3β, AXIN, and promotes the phosphorylation of β-catenin for proteasome degradation significantly. Furthermore, the nuclear accumulation of β-catenin and the DNA-binding activity of β-catenin/TCF/Lef complex are inhibited by 49.2% and 28.7%, respectively, when treated with 100 µM wogonoside. Taken together, our findings demonstrate that wogonoside is a potential inhibitor of tumor angiogenesis and can be developed as a therapeutic agent for breast cancer. © 2015 Wiley Periodicals, Inc.

Topics: Angiogenesis Inhibitors; Animals; Breast Neoplasms; Cell Line, Tumor; Female; Flavanones; Gene Expression Regulation, Neoplastic; Glucosides; Humans; MCF-7 Cells; Mice; Mice, Nude; Vascular Endothelial Growth Factor A; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Previous phytochemical studies showed that the major flavonoids in Scutellaria baicalensis are baicalin, baicalein, wogonoside and wogonin. The two glycosides (baicalin and wogonoside) can be transformed into their aglycons (baicalein and wogonin), which possess positive anticancer potential. In this study, we used glycosidase to catalyze flavonoids in S. baicalensis to enhance the herb's anticancer activities. Our HPLC data showed that, using the optimized conditions obtained in our experiments (20 U/g of cellulase, 50˚C, pH 4.8 and treatment for 8 h), there was a marked transformation from the two glycosides to their aglycons. The anticancer activity was subsequently evaluated using a series of S. baicalensis extracts in which variable lengths of glycosidase treatment time were used. Combining analytical and bioassay results, we observed that the higher the aglycon content, the stronger the antiproliferation effects. Compared to the untransformed control, 8 h of glycosidase catalyzing significantly increased antiproliferative activity on human colorectal and breast cancer cells, and its cancer cell growth inhibition is, in part, mediated by cell cycle arrest at the S-phase and induction of apoptosis. Data from this study suggest that using glycosidase to catalyze S. baicalensis offers a promising approach to increase its anticancer activity.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Female; Flavanones; Flavonoids; Glucosides; Glycoside Hydrolases; Humans; Phytotherapy; Plant Extracts; Scutellaria baicalensis

Previous studies have demonstrated that wogonoside, a bioactive flavonoid extracted from the root of Scutellaria baicalensis Gerogi, has anti-inflammatory and anti-angiogenic activities. In this study, we evaluated wogonoside-induced autophagy on human breast MDA-MB-231 cells. We report that wogonoside triggered the formation of microtubule-associated protein-light chain 3 (MAP-LC3) positive autophagosomes and the accumulation of acidic vesicular and autolysosomes in MDA-MB-231 cells. In addition, cells treated by wogonoside developed autophagosome-like characteristics, including single and double membrane vacuoles containing intact and degraded cellular debris. The results showed that wogonoside promotes the expression of LC3-II and Beclin-1. Furthermore, wogonoside inhibited cell growth of MDA-MB-231 cells in a concentration- and time-dependent manner, which was associated with wogonoside-induced autophagy. Wogonoside also suppressed the activation of mammalian target of rapamycin (mTOR) and p70-S6 kinase (p70S6K) by regulating the expression of the extracellular signal-regulated kinase (ERK1/2) and p38 involved mitogen-activated protein kinase (MAPK) signaling pathway. Taken together, these results suggest that wogonoside partially inhibits MDA-MB-231 cell growth by inducing autophagy through the MAPK-mTOR pathway and may be a promising anti-tumor agent.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Breast Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Female; Flavanones; Glucosides; Humans; Lysosomes; Membrane Proteins; Microtubule-Associated Proteins; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases; Vacuoles