AS1411 Nucleolin-Specific Binding Aptamers Reduce Pathological Angiogenesis through Inhibition of Nucleolin Phosphorylation

Abstract

Proliferative retinopathies produces an irreversible type of blindness affecting working age and pediatric population of industrialized countries. Despite the good results of anti-VEGF therapy, intraocular and systemic complications are often associated after its intravitreal use, hence novel therapeutic approaches are needed. The aim of the present study is to test the effect of the AS1411, an antiangiogenic nucleolin-binding aptamer, using in vivo, ex vivo and in vitro models of angiogenesis and propose a mechanistic insight. Our results showed that AS1411 significantly inhibited retinal neovascularization in the oxygen induced retinopathy (OIR) in vivo model, as well as inhibited branch formation in the rat aortic ex vivo assay, and, significantly reduced proliferation, cell migration and tube formation in the HUVEC in vitro model. Importantly, phosphorylated NCL protein was significantly abolished in HUVEC in the presence of AS1411 without affecting NFκB phosphorylation and -21 and 221-angiomiRs, suggesting that the antiangiogenic properties of this molecule are partially mediated by a down regulation in NCL phosphorylation. In sum, this new research further supports the NCL role in the molecular etiology of pathological angiogenesis and identifies AS1411 as a novel anti-angiogenic treatment.

Impairment of Nucleolin Activity and Phosphorylation by a Trachylobane Diterpene from Psiadia punctulata in Cancer Cells

“…However, it is interesting to note that a similar effect was also observed for AS1411, one of the most studied inhibitors of hNcl. Indeed, Iturriaga-Goyon et al showed that cellular treatment with this aptamer significantly and selectively reduced the phosphorylation of hNcl, slightly influencing the total protein level [ 41 ].…”

Nucleolin promotes angiogenesis and endothelial metabolism along the oncofetal axis in the human brain vasculature

“…Angiogenesis and the PVN exert crucial roles in the pathophysiology of various vascular-dependent CNS diseases such as brain tumors, vascular malformations, and stroke ( 6 , 7 , 17 , 49 , 50 , 56 ). With regard to brain tumors, glycosylated surface NCL has been shown to increase with the malignancy grade of human gliomas ( 99 ).…”

“…Nucleolin expression increases with malignancy grade and proliferation rate in both human and mouse glial brain tumors (42)(43)(44)(45), indicating its pro-proliferative role in glioma (see Supplementary Introduction). Targeting Nucleolin in cancer cells using the anti-Nucleolin aptamer AS1411 has been reported in brain and peripheral tumors (46)(47)(48), whereas AS1411-mediated targeting of Nucleolin in ECs of the pathological vasculature in the retina resulted in reduced angiogenicity (49,50). However, AS1411 has not been used to target Nucleolin in the vasculature of tumors in-and outside the CNS.…”

Synthesis and characterization of a glutathione-responsive drug delivery system based on aptamer-coated mesoporous silica

“…This structural feature contributes to the high affinity and specific binding of AS1411 to its target protein, nucleolin, which is highly expressed on the surfaces of many cancer cells but not on normal cells. Meanwhile, AS1411 is also the first aptamer to enter clinical oncology trials, demonstrating both anti-tumor activity and a notable absence of serious systemic toxicity (Soundararajan et al, 2009;Bates et al, 2009;Iturriaga-Goyon et al, 2021).…”