title: Vernolide-A inhibits radiation-induced hypoxia-mediated tumor angiogenesis by regulating HIF-1α, MMP-2, MMP-9, and VEGF.
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.
authors.affiliation: Amala Cancer Research Centre, Amala Nagar, Thrissur-680555, Kerala State, India.
authors.forename: P
authors.initials: P
authors.lastname: Pratheeshkumar
authors.forename: Girija
authors.initials: G
authors.lastname: Kuttan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C558651:vernolide-A; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9