Irreversible inhibition of CD13/aminopeptidase N by the antiangiogenic agent curcumin.
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.
Shim
Joong Sup
JS
Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, 143-747, Seoul, South Korea.
Kim
Jin Hee
JH
Cho
Hyun Young
HY
Yum
Young Na
YN
Kim
Seung Hee
SH
Park
Hyun-Ju
HJ
Shim
Bum Sang
BS
Choi
Seung Hoon
SH
Kwon
Ho Jeong
HJ
D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018826:CD13 Antigens / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015394:Molecular Structure
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016222:Fibroblast Growth Factor 2; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex; D003474:Curcumin