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ABSTRACT: Baicalin is the major component found in Scutellaria baicalensis root, a widely used herb in traditional Chinese medicine. Although it has been used for thousands of years to treat stroke, the mechanisms of action of S. baicalensis have not been clearly elucidated. In this report, we studied the modulation of angiogenesis as one possible mechanism by investigating the effects of these agents on expression of vascular endothelial growth factor (VEGF), a critical factor for angiogenesis.
The effects of baicalin and an extract of S. baicalensis on VEGF expression were tested in several cell lines. Both agents induced VEGF expression in all cells without increasing expression of hypoxia-inducible factor-1α (HIF-1α). The expression of reporter genes was also activated under the control of the VEGF promoter containing either a functional or a defective HIF response element (HRE). Only minimal effects were observed on reporter activation under the HRE promoter. Instead, both agents significantly induced oestrogen-related receptor (ERRα) expression as well as the activity of reporter genes under the control of ERRα-binding element. Their ability to induce VEGF expression was suppressed once ERRα expression was knocked down by siRNA or ERRα-binding sites were deleted in the VEGF promoter. We also found that both agents stimulated cell migration and vessel sprout formation from the aorta.
Our results implicate baicalin and S. baicalensis in angiogenesis by inducing VEGF expression through the activation of the ERRα pathway. These data may facilitate a better understanding of the potential health benefits of these agents in the treatment of cardiovascular diseases.
Cardiovascular research 02/2011; 89(2):426-35. · 5.80 Impact Factor
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Wei Liang,
Maciej Kujawski,
Jun Wu, Jianming Lu,
Andreas Herrmann,
Sofia Loera,
Yun Yen,
Frank Lee,
Hua Yu,
Wei Wen,
Richard Jove
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ABSTRACT: Several Src family kinase (SFK) inhibitors have entered clinical trials based on their direct effects against tumor cells. Here, we characterize the effects of targeting Src kinases on the tumor microenvironment and how these effects influence tumor growth.
Human cancer cells grown in cell culture or in mice were treated with dasatinib, a small-molecule inhibitor of SFKs. Tumor cell, endothelial cell, and myeloid cell compartments within the tumor microenvironment were analyzed. Primary human endothelial cells and freshly isolated CD11b+/CD11c- myeloid cells from mice were treated with dasatinib in cell culture. Cellular functions and signaling pathways affected by dasatinib were evaluated.
Dasatinib was not cytotoxic in cell culture against the human cancer cell lines investigated here. However, dasatinib administration in human tumor-bearing mice suppressed tumor growth associated with increased tumor cell apoptosis, decreased microvessel density, and reduced intratumoral CD11b+ myeloid cells. Dasatinib directly inhibited motility and other functions of endothelial and myeloid cells, accompanied by the inhibition of phosphorylation of SFKs and downstream signaling. Tumor-infiltrating myeloid cells were identified as the major source of matrix metalloproteinase (MMP)-9 in the tumor microenvironment. Dasatinib treatment reduced MMP-9 levels in the tumor microenvironment through the simultaneous inhibition of recruitment of MMP9+ myeloid cells and MMP-9 gene expression in tumor-infiltrating myeloid cells.
These findings suggest that Src kinase inhibitors such as dasatinib possess a previously unrecognized anticancer mechanism of action by targeting both host-derived endothelial and myeloid cell compartments within the tumor microenvironment.
Clinical Cancer Research 02/2010; 16(3):924-35. · 7.74 Impact Factor
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ABSTRACT: As a critical factor in the induction of angiogenesis, vascular endothelial growth factor (VEGF) has become an attractive target for anti-angiogenesis treatment. However, the side effects associated with most anti-VEGF agents limit their chronic use. Identification of naturally occurring VEGF inhibitors derived from diet is a potential alternative approach, with the advantage of known safety. To isolate natural inhibitors of VEGF, we established an in vitro tyrosine kinase assay to screen for diet-based agents that suppress VEGFR2 kinase activity. We found that a water-based extract from cinnamon (cinnamon extract, CE), one of the oldest and most popular spices, was a potent inhibitor of VEGFR2 kinase activity, directly inhibiting kinase activity of purified VEGFR2 as well as mitogen-activated protein kinase- and Stat3-mediated signaling pathway in endothelial cells. As a result, CE inhibited VEGF-induced endothelial cell proliferation, migration and tube formation in vitro, sprout formation from aortic ring ex vivo and tumor-induced blood vessel formation in vivo. Depletion of polyphenol from CE with polyvinylpyrrolidone abolished its anti-angiogenesis activity. While cinnamaldehyde, a component responsible for CE aroma, had little effect on VEGFR2 kinase activity, high-performance liquid chromatography-purified components of CE, procyanidin type A trimer (molecular weight, 864) and a tetramer (molecular weight, 1152) were found to inhibit kinase activity of purified VEGFR2 and VEGFR2 signaling, implicating procyanidin oligomers as active components in CE that inhibit angiogenesis. Our data revealed a novel activity in cinnamon and identified a natural VEGF inhibitor that could potentially be useful in cancer prevention and/or treatment.
Carcinogenesis 12/2009; 31(3):481-8. · 5.70 Impact Factor
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ABSTRACT: In addition to its essential role in ribonucleotide reduction, ribonucleotide reductase (RNR) small subunit, RRM2, has been known to play a critical role in determining tumor malignancy. Overexpression of RRM2 significantly enhances the invasive and metastatic potential of tumor. Angiogenesis is critical to tumor malignancy; it plays an essential role in tumor growth and metastasis. It is important to investigate whether the angiogenic potential of tumor is affected by RRM2.
We examined the expression of antiangiogenic thrombospondin-1 (TSP-1) and proangiogenic vascular endothelial growth factor (VEGF) in two RRM2-overexpressing KB cells: KB-M2-D and KB-HURs. We found that TSP-1 was significantly decreased in both KB-M2-D and KB-HURs cells compared to the parental KB and mock transfected KB-V. Simultaneously, RRM2-overexpressing KB cells showed increased production of VEGF mRNA and protein. In contrast, attenuating RRM2 expression via siRNA resulted in a significant increased TSP-1 expression in both KB and LNCaP cells; while the expression of VEGF by the two cells was significantly decreased under both normoxia and hypoxia. In comparison with KB-V, overexpression of RRM2 had no significant effect on proliferation in vitro, but it dramatically accelerated in vivo subcutaneous growth of KB-M2-D. KB-M2-D possessed more angiogenic potential than KB-V, as shown in vitro by its increased chemotaxis for endothelial cells and in vivo by the generation of more vascularized tumor xenografts.
These findings suggest a positive role of RRM2 in tumor angiogenesis and growth through regulation of the expression of TSP-1 and VEGF.
Molecular Cancer 03/2009; 8:11. · 3.99 Impact Factor
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ABSTRACT: Grape seed extract (GSE) is a widely consumed dietary supplement that has antitumor activity. Here, we have investigated the inhibitory effect of GSE on the expression of vascular endothelial growth factor (VEGF) and the mechanism underlying this action. We found that GSE inhibited VEGF messenger RNA (mRNA) and protein expression in U251 human glioma cells and MDA-MB-231 human breast cancer cells. GSE inhibited transcriptional activation of the VEGF gene through reducing protein but not mRNA expression of hypoxia-inducible factor (HIF) 1alpha. The inhibitory effect of GSE on HIF-1alpha expression was mainly through inhibiting HIF-1alpha protein synthesis rather than promoting protein degradation. Consistent with this result, GSE-suppressed phosphorylation of several important components involved in HIF-1alpha protein synthesis, such as Akt, S6 kinase and S6 protein. Furthermore, in the MDA-MB-231 tumor, we found that GSE treatment inhibited the expression of VEGF and HIF-1alpha and the phosphorylation of S6 kinase without altering the subcellular localization of HIF-1alpha, correlating with reduced vessel density and tumor size. Depletion of polyphenol with polyvinylpyrrolidone abolished the inhibitory activity of GSE, suggesting a water-soluble fraction of polyphenol in GSE is responsible for the inhibitory activity. Taken together, our results indicate that GSE inhibits VEGF expression by reducing HIF-1alpha protein synthesis through blocking Akt activation. This finding provides new insight into the mechanisms of anticancer activity of GSE and reveals a novel molecular mechanism underlying the antiangiogenic action of GSE.
Carcinogenesis 02/2009; 30(4):636-44. · 5.70 Impact Factor
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ABSTRACT: Blockade of angiogenesis is an important approach for cancer treatment and prevention. Vascular endothelial growth factor (VEGF) is one of the most critical factors that induce angiogenesis and has thus become an attractive target for antiangiogenesis treatment. However, most current anti-VEGF agents often cause some side effects when given chronically. Identification of naturally occurring VEGF inhibitors derived from diet would be one alternative approach with an advantage of known safety. Grape seed extract (GSE), a widely used dietary supplement, is known to have antitumor activity. In this study, we have explored the activity of GSE on VEGF receptor and angiogenesis. We found that GSE could directly inhibit the kinase activity of purified VEGF receptor 2, a novel activity of GSE that has not been characterized. GSE could also inhibit the VEGF receptor/mitogen-activated protein kinase-mediated signaling pathway in endothelial cells. As a result, GSE could inhibit VEGF-induced endothelial cell proliferation and migration as well as sprout formation from aorta ring. In vivo assay further showed that GSE could inhibit tumor growth and tumor angiogenesis of MDA-MB-231 breast cancer cells in mice. Consistent with the in vitro data, GSE treatment of tumor-bearing mice led to concomitant reduction of blood vessel density and phosphorylation of mitogen-activated protein kinase. Depletion of polyphenol with polyvinylpyrrolidone abolished the antiangiogenic activity of GSE, suggesting a water-soluble fraction of polyphenol in GSE is responsible for the antiangiogenic activity. Taken together, this study indicates that GSE is a well-tolerated and inexpensive natural VEGF inhibitor and could potentially be useful in cancer prevention or treatment.
Cancer Prevention Research 01/2009; 1(7):554-61. · 4.91 Impact Factor
