Vernolide-A inhibits tumour specific angiogenesis by regulating proinflammatory cytokines, VEGF, MMPs and TIMP

Angiogenesis is the development of new blood vessels from the pre-existing vascular beds, and plays a pivotal role in tumour growth, invasion and metastasis. We studied the antiangiogenic activity of vernolide-A using in vivo as well as in vitro models. Vernolide-A significantly inhibited tumour directed capillary formation. The level of serum proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and GM-CSF, and also level of serum VEGF, a proangiogenic factor were found to be elevated in angiogenesis induced animals which were significantly reduced by the treatment of vernolide-A in C57BL/6 mice. Administration of vernolide-A significantly enhanced the production of antiangiogenic factors such as IL-2 and TIMP. In vitro studies using rat aortic ring assay showed that vernolide-A at non-toxic concentrations significantly inhibited microvessel sprouting and also exhibited a significant inhibition in the proliferation, migration, and tube formation of endothelial cells, which are key events in the process of angiogenesis. Vernolide-A significantly inhibited the invasion of the collagen matrix by HUVECs in a dose dependent manner and also showed an inhibition in the activation of procollagenase to active collagenase of metalloproteinases. Taken together, these results demonstrate that vernolide-A inhibits tumour-specific angiogenesis by downregulating the production of pro-angiogenic factors like pro-inflammatory cytokines, VEGF, and MMPs and also upregulating the anti-angiogenic factors such as IL-2 and TIMP-1.