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- Title
Antiangiogenic and antihepatocellular carcinoma activities of the Juniperus chinensis extract.
- Authors
Zong-Keng Kuo; Mei-Wei Lin; I-Huang Lu; Hsin-Jan Yao; Hsin-Chieh Wu; Chun-Chung Wang; Shyh-Horng Lin; Si-Yuan Wu; Tien-Soung Tong; Yi-Cheng Cheng; Jui-Hung Yen; Ching-Huai Ko; Shu-Jiau Chiou; I-Horng Pan; Hsiang-Wen Tseng
- Abstract
Background: To identify a novel therapeutic agent for hepatocellular carcinoma (HCC), for which no promising therapeutic agent exists, we screened a panel of plants and found that Juniperus chinensis exhibited potential antiangiogenic and anti-HCC activities. We further investigated the antiangiogenic and anti-HCC effects of the active ingredient of J. chinensis extract, CBT-143-S-F6F7, both in vitro and in vivo. Methods: A tube formation assay conducted using human umbilical vein endothelial cells (HUVECs) was first performed to identify the active ingredient of CBT-143-S-F6F7. A series of angiogenesis studies, including HUVEC migration, Matrigel plug, and chorioallantoic membrane (CAM) assays, were then performed to confirm the effects of CBT-143-S-F6F7 on angiogenesis. The effects of CBT-143-S-F6F7 on tumor growth were investigated using a subcutaneous and orthotopic mouse model of HCC. In vitro studies were performed to investigate the effects of CBT-143-S-F6F7 on the cell cycle and apoptosis in HCC cells. Moreover, protein arrays for angiogenesis and apoptosis were used to discover biomarkers that may be influenced by CBT-143-S-F6F7. Finally, nuclear magnetic resonance analysis was conducted to identify the compounds of CBT-143-S-F6F7. Results: CBT-143-S-F6F7 showed significantly antiangiogenic activity in various assays, including HUVEC tube formation and migration, CAM, and Matrigel plug assays. In in vivo studies, gavage with CBT-143-S-F6F7 significantly repressed subcutaneous Huh7 tumor growth in severe combined immunodeficient (SCID) mice, and prolonged the survival of orthotopic Huh7 tumor-bearing SCID mice (a 40 % increase in median survival duration compared with the vehicle-treated mice). Immunohistochemical staining of subcutaneous Huh7 tumors in CBT-143-S-F6F7-treated mice showed a significantly decrease in the cell cycle regulatory protein cyclin D1, cellular proliferation marker Ki-67, and endothelial marker CD31. CBT-143-S-F6F7 caused arrest of the G2/M phase and induced Huh7 cell apoptosis, possibly contributing to the inhibition of HCC tumors. Protein array analysis revealed that several angiogenic and antiapoptotic factors were suppressed in CBT-143-S-F6F7-treated Huh7 cells. Finally, five compounds from CBT-143-S-F6F7 were identified. Conclusions: According to these results, we report for the first time the antiangiogenic and anti-HCC activities of CBT-143-S-F6F7, the active fractional extract of J. chinensis. We believe that CBT-143-S-F6F7 warrants further evaluation as a new anti-HCC drug.
- Subjects
ANIMAL experimentation; ANTINEOPLASTIC agents; BIOMARKERS; CELL culture; FLOW cytometry; HEPATOCELLULAR carcinoma; HIGH performance liquid chromatography; JUNIPERUS communis; MEDICINAL plants; MICE; MOLECULAR structure; NEOVASCULARIZATION inhibitors; RESEARCH funding; STATISTICAL sampling; SPECTROPHOTOMETRY; SURVIVAL analysis (Biometry); T-test (Statistics); PLANT extracts; DATA analysis software; DESCRIPTIVE statistics; KAPLAN-Meier estimator; IN vitro studies; IN vivo studies
- Publication
BMC Complementary & Alternative Medicine, 2016, Vol 16, p1
- ISSN
1472-6882
- Publication type
Article
- DOI
10.1186/s12906-016-1250-6