| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1994951 | Microvascular Research | 2011 | 9 Pages |
Our previous study revealed that LYP, a bestatin dimethylaminoethyl ester, inhibited the growth of human ovarian carcinoma ES-2 xenografts in mice and suppressed aminopeptidase N (APN/CD13) activity more potently than bestatin. In this study, we examined the inhibitory effect of LYP on migration and formation of capillary tube of human umbilical vascular endothelial cells (HUVECs) in vitro and anti-angiogenesis in ES-2 xenografts in mice. LYP did not possess cytotoxicity to HUVEC proliferation according to the MTT assay and trypan blue exclusion assay. However, APN/CD13 activity on cell surface of HUVECs was suppressed in the presence of LYP as measured by quantifying the enzymatic cleavage of the substrate l-leucine-p-nitroanilide. The assays of scratch and transwell chamber showed that LYP significantly inhibited HUVEC migration and invasion through Matrigel coated polycarbonate filters. Capillary tube formation assay revealed that the number of branch points formed by HUVECs on 3-D Matrigel was reduced after incubation with LYP. The anti-angiogenesis of LYP was verified in ES-2 xenografts in mice. The mean vascular density (MVD) and mean vascular luminal diameter (MVLD) were markedly reduced by LYP after two weeks of intravenous injection as evaluated by CD34 immunohistochemical staining. LYP suppression of cancer angiogenesis was greater than that of bestatin. The inhibition of angiogenic molecules may involve in anti-angiogenesis of LYP. The levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and transforming growth factor-alpha (TGF-α) were decreased in HUVECs and ES-2 xenografts after treatment with LYP as determined by Western blot analysis. These results indicated that the high efficacy of LYP may partially relate to the inhibition of angiogenesis.
Research highlights► We examined the antiangiogenic effect of a bestatin derivative LYP. ► LYP suppressed cell migration, capillary tube formation of HUVECs and angiogenesis in ES-2 xenografts. ► LYP inhibited APN/CD13 and expression of angiogenic molecules more potently than bestatin. ► LYP was superior to bestatin in inhibiting angiogenesis.
