curcumin and ubenimex

Aminopeptidase N (APN)/CD13 (EC 3.4.11.2) is a transmembrane protease present in a wide variety of human tissues and cell types (endothelial, epithelial, fibroblast, leukocyte). APN/CD13 expression is dysregulated in inflammatory diseases and in cancers (solid and hematologic tumors). APN/CD13 serves as a receptor for coronaviruses. Natural and synthetic inhibitors of APN activity have been characterized. These inhibitors have revealed that APN is able to modulate bioactive peptide responses (pain management, vasopressin release) and to influence immune functions and major biological events (cell proliferation, secretion, invasion, angiogenesis). Therefore, inhibition of APN/CD13 may lead to the development of anti-cancer and anti-inflammatory drugs. This review provides an update on the biological and pharmacological profiles of known natural and synthetic APN inhibitors. Current status on their potential use as therapeutic agents is discussed with regard to toxicity and specificity.

Topics: Animals; Betulinic Acid; CD13 Antigens; Cell Proliferation; Curcumin; Disulfides; Humans; Hydroxamic Acids; Leucine; Neovascularization, Physiologic; Neprilysin; Oligopeptides; Pentacyclic Triterpenes; Protease Inhibitors; Triterpenes; Tyrosine

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.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; CD13 Antigens; Cell Line; Cell Line, Tumor; Curcumin; Dose-Response Relationship, Drug; Fibroblast Growth Factor 2; Humans; Kinetics; Leucine; Molecular Structure