Abstract
BackgroundEpidemiological studies have shown that unfiltered coffee consumption is associated with a low incidence of cancer. This study aims to identify the effects of kahweol, an antioxidant diterpene contained in unfiltered coffee, on angiogenesis and key inflammatory molecules.Methodology/Principal FindingsThe experimental procedures included in vivo angiogenesis assays (both the chicken and quail choriallantoic membrane assay and the angiogenesis assay with fluorescent zebrafish), the ex vivo mouse aortic ring assay and the in vitro analysis of the effects of treatment of human endothelial cells with kahweol in cell growth, cell viability, cell migration and zymographic assays, as well as the tube formation assay on Matrigel. Additionally, two inflammation markers were determined, namely, the expression levels of cyclooxygenase 2 and the levels of secreted monocyte chemoattractant protein-1. We show for the first time that kahweol is an anti-angiogenic compound with inhibitory effects in two in vivo and one ex vivo angiogenesis models, with effects on specific steps of the angiogenic process: endothelial cell proliferation, migration, invasion and tube formation on Matrigel. We also demonstrate the inhibitory effect of kahweol on the endothelial cell potential to remodel extracellular matrix by targeting two key molecules involved in the process, MMP-2 and uPA. Finally, the anti-inflammatory potential of this compound is demonstrated by its inhibition of both COX-2 expression and MCP-1 secretion in endothelial cells.Conclusion/SignificanceTaken together, our data indicate that, indeed, kahweol behaves as an anti-inflammatory and anti-angiogenic compound with potential use in antitumoral therapies. These data may contribute to the explanation of the reported antitumoral effects of kahweol, including the recent epidemiological meta-analysis showing that drinking coffee could decrease the risk of certain cancers.
Highlights
Many different foods contain non-nutritional components that can have beneficial effects to the health [1]
Kahweol inhibits in vivo angiogenesis The chicken chorioallantoic membrane (CAM) assay was used to determine the ability of kahweol to inhibit angiogenesis in vivo
50 nmol of kahweol per CAM was required to observe in vivo inhibition of angiogenesis in 100% of treated eggs, as little as 10 nmol of kahweol was enough to induce clear inhibition of angiogenesis in 25% of the tested eggs in the CAM assay
Summary
Many different foods contain non-nutritional components that can have beneficial effects to the health [1] This is the case of coffee, which includes more than a thousand of compounds [2]. When quiescent endothelial cells are activated by some proangiogenic signal, they change their phenotype to become highly proliferative and able to migrate, remodel the surrounding extracellular matrix (ECM) and to differentiate to form new vessels. Any of these key steps can be a potential pharmacological target to inhibit angiogenesis and, to treat angiogenesisdependent diseases [9]. This study aims to identify the effects of kahweol, an antioxidant diterpene contained in unfiltered coffee, on angiogenesis and key inflammatory molecules
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