Vernolide-A inhibits radiation-induced hypoxia-mediated tumor angiogenesis by regulating HIF-1α, MMP-2, MMP-9, and VEGF

Amala Cancer Research Centre, Amala Nagar, Thrissur-680555, Kerala State, India.
Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer 01/2011; 30(2):139-51. DOI: 10.1615/JEnvironPatholToxicolOncol.v30.i2.50
Source: PubMed

ABSTRACT We investigated the effect of vernolide-A on the inhibition of radiation-induced tumor angiogenesis in C57BL/6 mice. Vernolide-A administration significantly reduced the tumor volume of radiation-exposed mice. Serum vascular endothelial growth factor (VEGF) levels were drastically elevated during tumor progression and irradiation and were significantly reduced by treatment with vernolide-A. Immunohistochemical analysis also revealed reduced vascular density after treatment with vernolide-A, and 3H-thymidine incorporation assay and soft agar assay showed that vernolide-A could inhibit the proliferation of B16F-10 melanoma cells in vitro along with radiation. Vernolide-A also caused a significant inhibition in the invasion of irradiated B16F-10 melanoma cells across the collagen matrix, and inhibited the radiation-induced gene expression of hypoxia-inducible transcription factor-1α (HIF-1α) and VEGF in B16F-10 cells and VEGF receptor (Flk-1) expression in human umbilical vein endothelial cells. Gelatin zymographic analysis showed that vernolide-A could also inhibit the radiation-induced activation of matrix metalloproteinases (MMPs). Our results indicate that vernolide-A inhibits radiation-induced tumor angiogenesis by regulating HIF-1α, MMP-2, MMP-9, and VEGF.

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    • "Telomere homolog oligonucleotides (T-oligos) act through Wermer and ataxia teleangiectasia mutated (ATM) kinase proteins and inhibit the activity of HIF-1, leading to decreased expression of VEGF, VEGF receptor 2, angiopoieitin-1, angiopoieitin-2. These oligos also decreased tumor vascularity in melanoma xenografts in immunocompromised mice.65 Vernolide-A inhibited radiation-induced tumor angiogenesis in B16F-10 melanoma cells in C57BL/6 mice through regulation of HIF-1α, metalloproteinases 2 and 9 and VEGF.66 It has been shown that berberine has anti-angiogenic effects in melanoma and it possibly acts through HIF-1α, VEGF and nitric oxide.67 "
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    ABSTRACT: Hypoxia-inducible factor-1α (HIF-1α) is a highly oxygen sensitive bHLH protein that is part of the heterodimeric HIF-1 transcription factor. Under hypoxic stress, HIF-1 activity is induced to control expression of multiple downstream target genes, including vascular endothelial growth factor (VEGF). The normal epidermis exists in a constant mild hypoxic microenvironment and constitutively expresses HIF-1α and HIF-2α. Expression of HIF-1α and/or HIF-2α has been suggested to correlate with the increased malignant potential of melanocytes, therefore, failures of melanoma therapies may be partially linked to high HIF activity. Notably, melanomas that have the V600E BRAF mutation exhibit increased HIF-1α expression. We have utilized a bioinformatics approach to identify putative hypoxia response elements (HREs) in a set of genes known to participate in the process of melanogenesis (includingTRPM1, SLC45A2, HRAS, C-KIT, PMEL and CRH). While some of the mechanistic links between these genes and the HIF pathway have been previously explored, others await further investigation. Although agents targeting HIF activity have been proposed as novel treatment modalities for melanoma, there are currently no clinical trials in progress to test their efficacy in melanoma.
    Dermato-Endocrinology 04/2013; 5(2):239-251. DOI:10.4161/derm.22678
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    • "Much attention has been given to the Phase I/II trial of carboplatin, taxol and sorafenib (Nexavar, Bayer Pharmaceuticals Corporation, West Haven, CT and Onyx Pharmaceuticals, Emeryville, CA), a multi-tyrosine kinase inhibitor with activity against both the MAP kinase and VEGF-R2-signalling pathways (Mehnert et al, 2010). Additional ongoing trials of novel agents that target VEGF and its receptors include also the study of Vernolide-A (Pratheeshkumar and Kuttan, 2011) that in B16F-10 melanoma cells inhibit tumour angiogenesis by regulating HIF-1a, MMP-2, MMP-9 and VEGF. "
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    ABSTRACT: Objective: To understand the role of angiogenesis and hypoxia in cancer progression of primary oral melanoma (POM). Materials and methods: Sixteen malignant primary melanomas were immunostained with markers CD34, VEGF and HIF-1α. Stained cells were counted in the invasive front and inside the tumour, and the differences were compared and correlated with histological parameters and disease-specific survival of the patients. Results: Tumour invasive front showed increased MVD and increased vessel VEGF and HIF-1α expression compared with the intratumoural compartment. No such differences were seen in tumoural melanocytes of the two compartments. Positive correlations were observed between CD34 and VEGF, CD34 and HIF-1α and VEGF and HIF-1α expression in invasive front vessels. CD34 expression was statistically correlated with the level of infiltration. A significant trend to worse disease-free survival was also determined with increased invasive front vessel expression of CD34, VEGF and HIF-1α. Conclusions: Our data highlight the importance of the invasive margin in POM biology. The high angiogenic activity and endothelial VEGF and HIF-1α expression in invasive front vessels have a significant impact on patient survival and future agents targeted against VEGF pathway may represent a novel and effective therapeutic opportunity. Larger studies are needed to further address our findings.
    Oral Diseases 12/2012; 19(6). DOI:10.1111/odi.12048 · 2.43 Impact Factor
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    ABSTRACT: Matrix metalloproteinases (MMPs) have been involved in inflammatory and degradative processes in pathologic conditions. The purpose of this study was to investigate the protective effect of melatonin in human umbilical vein endothelial cell (HUVEC) monolayer permeability and the regulation of MMP9 induced by interleukin 1β (IL1β (IL1B)) in HUVECs. Protection studies were carried out with melatonin, a well-known antioxidant and antiinflammatory molecule. MMP9 expression was increased with IL1β induction in HUVECs. Melatonin showed a barrier-protective role by downregulation of MMP9 and upregulation of tissue inhibitor of metalloproteinase-1 expression in HUVECs. Meanwhile, melatonin also decreased sodium fluorescein permeability and counteracted the downregulation of vascular endothelial cadherin and occludin expression in HUVECs. During inflammatory stimulus, nuclear factor-κB (NF-κB) plays a significant role in regulating MMP genes expression, thus the function of NF-κB in HUVECs' barrier disruption was investigated. IL1β induced nuclear translocation of NF-κB in HUVECs and regulated MMP9 expression. However, NF-κB translocation into the nucleus was inhibited significantly by melatonin. Our results show that melatonin decreases the permeability of monolayer endothelial cell induced by IL1β. At the same time, melatonin decreased the expression and activity of MMP9 by a NF-κB-dependent pathway in HUVECs induced by IL1β.
    Journal of Endocrinology 05/2012; 214(2):145-53. DOI:10.1530/JOE-12-0147 · 3.72 Impact Factor
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