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Background  Cyclic RGD peptidomimetics containing a bifunctional diketopiperazine scaffold are a novel class of high-affinity ligands for the integrins α V β 3  and α V β 5 . Since integrins are a promising target for the modulation of normal and pathological angiogenesis, the present study aimed at characterizing the ability of the RGD peptidomimetic  cyclo [DKP-RGD]  1  proliferation, migration and network formation in human umbilical vein endothelial cells (HUVEC).    Methods  Cell viability was assessed by flow cytometry and annexin V (ANX)/propidium iodide (PI) staining. Cell proliferation was evaluated by the ELISA measurement of bromodeoxyuridine (BrdU) incorporation. Network formation by HUVEC cultured in Matrigel-coated plates was evaluated by optical microscopy and image analysis. Integrin subunit mRNA expression was assessed by real time-PCR and Akt phosphorylation by western blot analysis.    Results   Cyclo [DKP-RGD]  1  does not affect cell viability and proliferation either in resting conditions or in the presence of the pro-angiogenic growth factors VEGF, EGF, FGF, and IGF-I. Addition of  cyclo [DKP-RGD]  1  however significantly decreased network formation induced by pro-angiogenic growth factors or by IL-8.  Cyclo [DKP-RGD]  1  did not affect mRNA levels of α V , β 3  or β 5  integrin subunits, however it significantly reduced the phosphorylation of Akt.    Conclusions   Cyclo [DKP-RGD]  1  can be a potential modulator of angiogenesis induced by different growth factors, possibly devoid of the adverse effects of cytotoxic RGD peptidomimetic analogues.

Effects of a novel cyclic RGD peptidomimetic on cell proliferation, migration and angiogenic activity in human endothelial cells