Irreversible Inhibition of CD13/Aminopeptidase N by the Antiangiogenic Agent Curcumin

Abstract

CD13/aminopeptidase N (APN) is a membrane-bound, zinc-dependent metalloproteinase that plays a key role in tumor invasion and angiogenesis. Here, we show that curcumin, a phenolic natural product, binds to APN and irreversibly inhibits its activity. The direct interaction between curcumin with APN was confirmed both in vitro and in vivo by surface plasmon resonance analysis and an APN-specific antibody competition assay, respectively. Moreover, curcumin and other known APN inhibitors strongly inhibited APN-positive tumor cell invasion and basic fibroblast growth factor-induced angiogenesis. However, curcumin did not inhibit the invasion of APN-negative tumor cells, suggesting that the antiinvasive activity of curcumin against tumor cells is attributable to the inhibition of APN. Taken together, our study revealed that curcumin is a novel irreversible inhibitor of APN that binds to curcumin resulting in inhibition of angiogenesis.

Curcumin as “Curecumin”: From kitchen to clinic

“…By directly binding small b-amyloid species, curcumin blocks aggregation and fibril formation in vitro and in vivo [51]. Curcumin irreversibly binds CD13/aminopeptidase N (APN) and inhibits tumor invasion and angiogenesis [55]. Curcumin has also been shown to inhibit the activity of lipoxygenase by binding lipoxygenase itself [65] or binding to phosphatidylcholine (PC) micelles and thereby inhibiting lipoxygenase 1 [74].…”

Efficient delivery of angiostatin K1-5 into tumors following insertion of an NGR peptide into adenovirus capsid

“…Pre-incubation with curcumin, an uncompetitive inhibitor, 34 was shown to block more than 85% of CD13 receptors (inset), leading to decreased b-gal expression in AdHNGR-infected Lewis lung carcinoma (LLC) (Figure 3a high SLK cells (black) were more efficiently transduced by AdHNGR than CD13 low SLK cells (gray). Finally, the role of CD13 was investigated using LLC cells infected with lentiviral vectors expressing either scramble shRNA or shRNA-targeting CD13.…”

Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1

“…Recently, curcumin was shown to inhibit vascular endothelial cell proliferation in vitro and capillary tube formation in vivo (16)(17)(18)(19). These studies demonstrated that the potent chemopreventive activity of curcumin may, in part, be derived from the direct inhibition of angiogenesis.…”