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ABSTRACT: Tumor growth depends on angiogenesis and inducing angiogenesis is one of the most important hallmarks in the cancer development. Treatment with small molecules that inhibit angiogenesis has been an effective strategy for anti-cancer therapy. Some anti-angiogenic factors are derived from traditional Chinese herbs. Usnic acid (UA), an active compound mainly found in lichens, has shown some biological and physiological activities. However, the role and mechanism of UA in tumor angiogenesis are still unknown. The aim of this study was to assess the effects of UA on tumor angiogenesis. In this study, we demonstrated that UA strongly inhibited in vivo angiogenesis in a chick embryo chorioallantoic membrane assay and vascular endothelial growth factor-induced mouse corneal angiogenesis model. In a mouse xenograft tumor model, UA suppressed Bcap-37 breast tumor growth and angiogenesis without affecting mice body weight. In an in vitro assay, UA not only significantly inhibited endothelial cell proliferation, migration and tube formation, but also induced morphological changes and apoptosis in endothelial cells. In addition, UA inhibited Bcap-37 tumor cell proliferation. Moreover, western blot analysis of cell signaling molecules indicated that UA blocked vascular endothelial growth factor receptor (VEGFR) 2 mediated Extracellular signal-regulated protein kinases 1 and 2(ERK1/2) and AKT/P70S6K signaling pathways in endothelial cells. These results provided the first evidence of the biological function and molecular mechanism of UA in tumor angiogenesis.
Angiogenesis 04/2012; 15(3):421-32. · 6.06 Impact Factor
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Li Lai,
Junchen Liu,
Dong Zhai,
Qingxiang Lin,
Lijun He,
Yanmin Dong,
Jing Zhang, Binbin Lu,
Yihua Chen,
Zhengfang Yi,
Mingyao Liu
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ABSTRACT: Angiogenesis-based therapy is an effective anti-tumour strategy and previous reports have shown some beneficial effects of a naturally occurring bioactive compound plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone). Here, we sought to determine the biological effects of plumbagin on signalling mechanisms during tumour angiogenesis.
The effects of plumbagin were evaluated in various in vitro assays which utilised human umbilical vein endothelial cells (HUVEC) proliferation, migration and tube formation. Plumbagin was also evaluated in vivo using chicken embryo chorioallantoic membrane (CAM) and mouse corneal micropocket models., Human colon carcinoma and prostate cancer xenograft mouse models were used to evaluate the effects of plumbagin on angiogenesis. Immunofluorescence, GST pull-down and Western blotting were employed to explore the underlying mechanisms of VEGF receptor (VEGFR)2-mediated Ras signalling pathways.
Plumbagin not only inhibited endothelial cell proliferation, migration and tube formation but also suppressed chicken chorioallantoic membrane neovascularzation and VEGF-induced mouse corneal angiogenesis. Moreover, plumbagin suppressed tumour angiogenesis and tumour growth in human colon carcinoma and prostate cancer xenograft mouse models. At a molecular level, plumbagin blocked the Ras/Rac/cofilin and Ras/MEK signalling pathways mediated by VEGFR2 in HUVECs.
Plumbagin inhibited tumour angiogenesis and tumour growth by interference with the VEGFR2-mediated Ras signalling pathway in endothelial cells. Our findings demonstrate a molecular basis for the effects of plumbagin and suggest that this compound might have therapeutic ant-tumour effects.
British Journal of Pharmacology 06/2011; 165(4b):1084-96. · 4.41 Impact Factor
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ABSTRACT: (-)-Gossypol, a natural BH3-mimetic and small-molecule Bcl-2 inhibitor, shows promise in ongoing phase II clinical trials for human cancers. However, whether (-)-gossypol plays functional roles in tumor angiogenesis has not been directly elucidated yet. In this study, we showed that (-)-gossypol dose dependently inhibited the expression of VEGF, Bcl-2, and Bcl-xL in human prostate cancer cells (PC-3 and DU 145) and primary cultured human umbilical vascular endothelial cells (HUVEC) in vitro. Notably, the growth of human prostate tumor PC-3 xenografts in mice was significantly suppressed by (-)-gossypol at a dosage of 15 mg/kg/d. This inhibitory action of (-)-gossypol in vivo was largely dependent on suppression of angiogenesis in the solid tumors, where VEGF expression and microvessel density were remarkably decreased. Furthermore, (-)-gossypol inhibited VEGF-induced chemotactic motility and tubulogenesis in HUVECs and human microvascular endothelial cells and suppressed microvessel sprouting from rat aortic rings ex vivo. When examined for the mechanism, we found that (-)-gossypol blocked the activation of VEGF receptor 2 kinase with the half maximal inhibitory concentration of 2.38 μmol/L in endothelial cells. Consequently, the phosphorylation of key intracellular proangiogenic kinases induced by VEGF was all suppressed by the treatment, such as Src family kinase, focal adhesion kinase, extracellular signal-related kinase, and AKT kinase. Taken together, the present study shows that (-)-gossypol potently inhibits human prostate tumor growth through modulating VEGF signaling pathway, which further validates its great potential in clinical practice.
Molecular Cancer Therapeutics 03/2011; 10(5):795-805. · 5.23 Impact Factor
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Xiaoli Zhang,
Yajuan Song,
Yuanyuan Wu,
Yanmin Dong,
Li Lai,
Jing Zhang, Binbin Lu,
Fujun Dai,
Lijun He,
Mingyao Liu,
Zhengfang Yi
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ABSTRACT: Tumor angiogenesis is one of the hallmarks of the development in malignant neoplasias and metastasis. Many angiogenesis inhibitors are small molecules from natural products. Indirubin, the active component of a traditional Chinese herbal medicine, Banlangen, has been shown to exhibit antitumor and anti-inflammation effects. But its roles in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is unknown. Here, we identified that indirubin inhibited prostate tumor growth through inhibiting tumor angiogenesis. Using chick chorioallantoic membrane (CAM) assay and mouse corneal model, we found that indirubin inhibited angiogenesis in vivo. We also showed the inhibition activity of indirubin in endothelial cell migration, tube formation and cell survival in vitro. Furthermore, indirubin suppressed vascular endothelial growth factor receptor 2-mediated Janus kinase (JAK)/STAT3 signaling pathway but had little effects on the activity of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase in endothelial cell. Our study provided the first evidence for antitumor angiogenesis activity of indirubin and the related molecular mechanism. Our investigations suggested that indirubin was a potential drug candidate for angiogenesis related diseases.
International Journal of Cancer 01/2011; 129(10):2502-11. · 5.44 Impact Factor
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Yanmin Dong, Binbin Lu,
Xiaoli Zhang,
Jing Zhang,
Li Lai,
Dali Li,
Yuanyuan Wu,
Yajuan Song,
Jian Luo,
Xiufeng Pang,
Zhengfang Yi,
Mingyao Liu
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ABSTRACT: Cucurbitacin E (CuE, α-elaterin), a tetracyclic triterpenes compound from folk traditional Chinese medicine plants, has been shown to inhibit cancer cell growth, inflammatory response and bilirubin-albumin binding. However, the effects of CuE on tumor angiogenesis and its potential molecular mechanism are still unknown. Here, we demonstrated that CuE significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration and tubulogenesis in vitro and blocked angiogenesis in chick embryo chorioallantoic membrane assay and mouse corneal angiogenesis model in vivo. Furthermore, we found that CuE remarkably induced HUVEC apoptosis, inhibited tumor angiogenesis and suppressed human prostate tumor growth in xenograft tumor model. Finally, we showed that CuE blocked vascular endothelial growth factor receptor (VEGFR) 2-mediated Janus kinase (Jak) 2-signal transducer and activator of transcription (STAT) 3 signaling pathway in endothelial cells and suppressed the downstream protein kinases, such as extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Therefore, our studies provided the first evidence that CuE inhibited tumor angiogenesis by inhibiting VEGFR2-mediated Jak-STAT3 and mitogen-activated protein kinases signaling pathways and CuE is a potential candidate in angiogenesis-related disease therapy.
Carcinogenesis 12/2010; 31(12):2097-104. · 5.70 Impact Factor
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ABSTRACT: Understanding the molecular basis and target of traditional medicine is critical for drug development. Celastrol, derived from Trypterygium wilfordii Hook F. ("Thunder of God Vine"), a traditional Chinese medicine plant, has been assigned anticancer activities, but its mechanism is not well understood. Here, we investigated whether Celastrol could inhibit angiogenesis-mediated tumor growth and, if so, through what mechanism. When given s.c. to mice bearing human prostate cancer (PC-3 cell) xenografts, Celastrol (2 mg/kg/d) significantly reduced the volume and the weight of solid tumors and decreased tumor angiogenesis. We found that this agent inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion, and capillary-like structure formation by primary cultured human umbilical vascular endothelial cells (HUVEC) in a dose-dependent manner. Furthermore, Celastrol abrogated VEGF-induced sprouting of the vessels from aortic rings and inhibited vascular formation in the Matrigel plug assay in vivo. To understand the molecular mechanism of these activities, we next examined the signaling pathways in treated HUVECs and PC-3 tumor cells. Celastrol suppressed the VEGF-induced activation of AKT, mammalian target of rapamycin (mTOR), and ribosomal protein S6 kinase (P70S6K). Additionally, we found that Celastrol inhibited the proliferation of prostate cancer cells and induced apoptosis, and these effects correlated with the extent of inhibition of AKT/mTOR/P70S6K signaling. Taken together, our results suggest that Celastrol targets the AKT/mTOR/P70S6K pathway, which leads to suppression of tumor growth and angiogenesis.
Cancer Research 02/2010; 70(5):1951-9. · 7.86 Impact Factor
