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.
Amala Cancer Research Centre, Amala Nagar, Thrissur-680555, Kerala State, India.
Poyil
P
Pratheeshkumar
Girija
G
Kuttan
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D004586:Electrophoresis; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005780:Gelatin / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D016207:Cytokines; D012717:Sesquiterpenes; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D042461:Vascular Endothelial Growth Factor A; C558651:vernolide-A; D005780:Gelatin; D020782:Matrix Metalloproteinases