Vernolide-A Inhibits Radiation-Induced Hypoxia-Mediated Tumor Angiogenesis by Regulating HIF-1 alpha, MMP-2, MMP-9, and VEGF

We investigated the effect of vemolide-A on the inhibition of radiation-induced tumor angiogenesis in C57BL/6 mice. Vemolide-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 vemolide-A. Immunohistochemical analysis also revealed reduced vascular density after treatment with vernolide-A, and (3)H-thymidine incorporation assay and soft agar assay showed that vemolide-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-1 alpha (HIF-1 alpha) and VEGF in B16F-10 cells and VEGF receptor (Flk-1) expression in human umbilical vein endothelial cells. Gelatin zymographic analysis showed that vemolide-A could also inhibit the radiation-induced activation of matrix metalloproteinases (MMPs). Our results indicate that vemolide-A inhibits radiation-induced tumor angiogenesis by regulating HIF-1 alpha, MMP-2, MMP-9, and VEGF.