Inhibition of metastasis, angiogenesis, and tumor growth by Chinese herbal cocktail Tien-Hsien Liquid.
BACKGROUND
Advanced 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.


METHODS
The 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-1alpha and the phosphorylation of ERK1/2 were determined by Western blot.


RESULTS
THL 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-1alpha 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.


CONCLUSIONS
Our data demonstrate that THL had broad-spectra anti-cancer activities and merits further evaluation for its use in cancer therapy.
Chia
Jean-San
JS
Graduate Institute of Microbiology, National Taiwan University, Taipei 100, Taiwan.
Du
Jia-Ling
JL
Hsu
Wei-Bin
WB
Sun
Andy
A
Chiang
Chun-Pin
CP
Wang
Won-Bo
WB
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D013997:Time Factors; D047368:Tumor Burden; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C492794:tien-hsien liquid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9