The designer antiangiogenic peptide anginex targets tumor endothelial cells and inhibits tumor growth in animal models

Abstract

The de novo designed angiogenesis inhibitor anginex was tested in vitro and in vivo for its mechanism of action and antitumor activity. The data presented here demonstrate that anginex is a powerful antiangiogenic agent with significant antitumor activity. The mechanism of action of anginex was found to be the induction of anoikis leading to apoptosis in angiogenically activated endothelial cells, resulting in an up to 90% inhibition of migration in the wound assay. Anginex inhibited angiogenesis as demonstrated in the in vitro mouse aortic ring assay. In addition, tumor-induced angiogenesis in the chick chorioallantoic membrane was markedly inhibited. Anginex showed profound antitumor activity in the syngeneic mouse B16F10 melanoma model and in a xenograft human tumor model. Microvessel density determination as well as magnetic resonance imaging showed that the antitumor activity in these tumor models resulted from the antiangiogenic activity of anginex. A complete absence of toxicity was observed in these models. The data presented here demonstrate that anginex is a promising agent for further clinical development.

Anginex synergizes with radiation therapy to inhibit tumor growth by radiosensitizing endothelial cells

“…[18][19][20] Apparently, this function of anginex makes tumor tissue more susceptible to radiation and reduces the ability of tumors to recover from radiation, thereby explaining the results of the tumor growth delay assays presented here. In this regard, the in vivo and in vitro studies presented here strongly suggest that anginex actually sensitizes EC to radiation treatment.…”

“…Anginex was already known to specifically target EC in newly forming blood vessels in tumors 19 and, as with other antiangiogenics, to reduce MVD in tumors. [18][19][20] Apparently, this function of anginex makes tumor tissue more susceptible to radiation and reduces the ability of tumors to recover from radiation, thereby explaining the results of the tumor growth delay assays presented here.…”

“…Recently, we reported the design of anginex, a b-sheet forming peptide 33mer, with potent in vitro 17 and in vivo 18,19 antiangiogenesis activity. Anginex is water soluble, shelf-stable, and nontoxic in animals.…”

In vitro assays of angiogenesis for assessment of angiogenic and anti-angiogenic agents

“…Angiogenic outgrowth occurs over a shorter time period with the mouse aortic rings (Masson et al, 2002), and both angiogenic and anti-angiogenic factors can be assessed (e.g. Kojima et al, 2007;van der Schaft et al, 2002). Each mouse yields fewer aortic rings than does a rat, however, and removal of the adventitial surrounding the aorta is more difficult with these smaller vessels.…”

Dynamic contrast-enhanced magnetic resonance imaging at 1.5 Tesla with gadopentetate dimeglumine to assess the angiostatic effects of anginex in mice

“…In vivo anginex targets angiogenically activated (tumour) endothelial cells and inhibits angiogenesis, ultimately leading to anticancer activity in mice, both as a single therapy and in combination with chemotherapy [4], with no toxic effects observed thus far [5].…”