vernolide-a and Neoplasms

Bioassay-guided fractionation of the hexane extract from the flowers of Vernonia cinerea (Asteraceae) led to the isolation of a new sesquiterpene lactone, 8α-hydroxyhirsutinolide (2), and a new naturally occurring derivative, 8α-hydroxyl-1-O-methylhirsutinolide (3), along with seven known compounds (1 and 4-9). The structures of the new compounds were determined by 1D and 2D NMR experiments and by comparison with the structure of compound 1, whose relative stereochemistry was determined by X-ray analysis. The isolated compounds were evaluated for their cancer chemopreventive potential based on their ability to inhibit nitric oxide (NO) production and tumor necrosis factor alpha (TNF-α)-induced NF-κB activity. Compounds 1, 2, 4, 5, and 9 inhibited TNF-α-induced NF-κB activity with IC(50) values of 3.1, 1.9, 0.6, 5.2, and 1.6 μM, respectively; compounds 4 and 6-9 exhibited significant NO inhibitory activity with IC(50) values of 2.0, 1.5, 1.2, 2.7, and 2.4 μM, respectively.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Crystallography, X-Ray; Flowers; Humans; Lactones; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Neoplasms; NF-kappa B; Nitric Oxide; Plant Extracts; Sesquiterpenes; Tumor Necrosis Factor-alpha; Vernonia

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.

Topics: Angiogenesis Inhibitors; Animals; Aorta; Capillaries; Cell Movement; Cell Proliferation; Cytokines; Electrophoresis; Endothelial Cells; Gelatin; Humans; Inflammation; Male; Matrix Metalloproteinases; Mice; Molecular Structure; Neoplasms; Neovascularization, Pathologic; Rats; Sesquiterpenes; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinases; Vascular Endothelial Growth Factor A