Abstract
Sylvest L, Bendiksen CD, Houen G. Phosphatase inhibitors with anti-angiogenic effect in vitro. APMIS 2010; 118: 49–59.Levamisole has previously been identified as an inhibitor of angiogenesis in vitro and in vivo, but the mechanism behind the anti-angiogenic behavior has not yet been established. However, one known effect of levamisole is the inhibition of alkaline phosphatase, and this fact encouraged us to test other phosphatase inhibitors for their anti-angiogenic effects by using the same method as used to identify levamisole: an ELISA-based co-culture angiogenesis assay giving quantitative and qualitative results. Historically, intracellular phosphatases have been associated with the downregulation of signaling pathways, and kinases with their upregulation, but lately, the phospatases have also been coupled to positive signaling, which is why inhibition of phosphatases has become associated with anti-tumorigenic and anti-angiogenic effects. The results obtained in this work reveal several agents with anti-angiogenic potential and give a strong indication that phosphatase inhibition is linked to anti-angiogenic activity. An apparent disruption of endothelial tube formation was seen for seven of eight phosphatase inhibitors tested in the angiogenesis assay. By looking at the morphological results, it was seen that most of the inhibitors impaired proliferation and elongation of the endothelial cells, which still had a differentiated appearance. One inhibitor, PTP inhibitor IV, seemed to impair endothelial cell differentiation and induced the same morphology as when cells were treated with levamisole, although at a 200 times lower concentration than that of levamisole. Hence, our work points out compounds with a potential that may be of use in the search for new medical products for the treatment of malignant tumors, or other conditions where angiogenesis plays a central role.
Highlights
Levamisole has previously been identified as an inhibitor of angiogenesis in vitro and in vivo, but the mechanism behind the anti-angiogenic behavior has not yet been established
Angiogenesis involves the coordination of several steps: (i) binding of angiogenic stimulating factors [vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)] to their receptors on endothelial cells, (ii) secretion of proteases, which degrade the vascular basement membrane (VBM) and the surrounding extracellular matrix (ECM), (iii) endothelial proliferation and migration, (iv) endothelial differentiation and tube formation, (v) reformation of the VBM, (vi) recruitment of pericytes, which surround and stabilize the newly formed vessel [4,5,6]
The work covered in this article describes different phosphatase inhibitors (Table 1) that were assayed for the effect on endothelial cell network formation in an in vitro co-culture angiogenesis assay
Summary
Levamisole has previously been identified as an inhibitor of angiogenesis in vitro and in vivo, but the mechanism behind the anti-angiogenic behavior has not yet been established. One known effect of levamisole is the inhibition of alkaline phosphatase, and this fact encouraged us to test other phosphatase inhibitors for their anti-angiogenic effects by using the same method as used to identify levamisole: an ELISA-based co-culture angiogenesis assay giving quantitative and qualitative results. By looking at the morphological results, it was seen that most of the inhibitors impaired proliferation and elongation of the endothelial cells, which still had a differentiated appearance. The inhibitors have been seen to cause serious side effects [9,10,11], and identification of new angiogenesis inhibitors with limited toxicity and a broader efficiency is still needed, as well as a further understanding of endothelial cell signaling to comprehend the mechanisms of action of potential inhibitors
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