Abstract
BackgroundAdvanced cancer is a multifactorial disease that demands treatments targeting multiple cellular pathways. Chinese herbal cocktail which contains various phytochemicals may target multiple dys-regulated pathways in cancer cells and thus may provide an alternative/complementary way to treat cancers. Previously we reported that the Chinese herbal cocktail Tien-Hsien Liguid (THL) can specifically induce apoptosis in various cancer cells and have immuno-modulating activity. In this study, we further evaluated the anti-metastatic, anti-angiogenic and anti-tumor activities of THL with a series of in vitro and in vivo experiments.MethodsThe migration and invasion of cancer cells and endothelial cells was determined by Boyden chamber transwell assays. The effect of THL on pulmonary metastasis was done by injecting CT-26 colon cancer cells intravenously to syngenic mice. The in vitro and in vivo microvessel formation was determined by the tube formation assay and the Matrigel plug assay, respectively. The in vivo anti-tumor effect of THL was determined by a human MDA-MB-231 breast cancer xenograft model. The expression of metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) was measured by gelatin zymography. The expression of HIF-1α and the phosphorylation of ERK1/2 were determined by Western blot.ResultsTHL inhibited the migration and invasion ability of various cancer cells in vitro, decreased the secretion of MMP-2, MMP-9, and uPA and the activity of ERK1/2 in cancer cells, and suppressed pulmonary metastasis of CT-26 cancer cells in syngenic mice. Moreover, THL inhibited the migration, invasion, and tube formation of endothelial cells in vitro, decreased the secretion of MMP-2 and uPA in endothelial cells, and suppressed neovascularization in Matrigel plugs in mice. Besides its inhibitory effect on endothelial cells, THL inhibited hypoxia-induced HIF-1α and vascular endothelial growth factor-A expression in cancer cells. Finally, our results show that THL inhibited the growth of human MDA-MB-231 breast cancer xenografts in NOD-SCID mice. This suppression of tumor growth was associated with decreased microvessel formation and increased apoptosis caused by THL.ConclusionOur data demonstrate that THL had broad-spectra anti-cancer activities and merits further evaluation for its use in cancer therapy.
Highlights
Advanced cancer is a multifactorial disease that demands treatments targeting multiple cellular pathways
After 20 h incubation, the gap remained unfilled by the migrated cells in the Tien-Hsien Liguid (THL)-treated group was wider than that in the untreated group (Fig 1A, right panel), indicating that THL can inhibit the motility of Pogostemon cablin (PC)-3 cancer cells
We tested the effect of THL on the migration of MDA-MB-231, H1299, PC-3, and CT-26 cancer cells by the Boyden chamber transwell assay
Summary
Advanced cancer is a multifactorial disease that demands treatments targeting multiple cellular pathways. Local hypoxic conditions induce a molecular response in tumor cells, leading to the activation of a key transcription factor, the hypoxia-inducible factor (HIF) [9]. This transcription factor induces the expression of pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF), which in turn bind to and activate their respective receptors on the surface of endothelial cells, leading to angiogenesis [10,11]. Since angiogenesis plays a prominent role in tumor growth and metastasis, inhibition of angiogenesis is considered to be an important strategy for cancer therapy [12,13]
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