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September 1, 2003
Volume 81, Number 35
CENEAR 81 35 p. 8
ISSN 0009-2347


BIOCHEMISTRY

HOW CURRY COMBATS CANCER
The active ingredient curcumin inhibits an enzyme that promotes tumors

LOUISA DALTON

Biochemists in South Korea have discovered how curcumin fights cancer. Curcumin, the bright yellow active ingredient in turmeric (a spice used in curry), irreversibly inhibits aminopeptidase N (APN), an enzyme that spurs tumor invasiveness and angiogenesis (blood vessel growth) [Chem. Biol., 10, 695 (2003)].

Scientists have known since the early 1990s that curcumin somehow slows the growth of new cancers. With further study, it was found to arrest angiogenesis. Curcumin is now in Phase I clinical trials for colon cancer.

Ho Jeong Kwon, professor of bioscience and biotechnology at Sejong University, Seoul, wasn't initially thinking about curcumin when he and his laboratory embarked on a large-scale chemical genetics effort to isolate antiangiogenic agents. They were looking at APN, a newly identified player in angiogenesis. APN is a membrane-bound, zinc-dependent metalloproteinase that breaks down proteins at the cell surface and helps cancer cells invade the space of neighboring cells. Kwon's laboratory screened 3,000 molecules for activity against APN, and curcumin showed up as a potent inhibitor.

Through a combination of in vitro and in vivo enzyme assays and surface plasmon resonance analysis, Kwon and coworkers established that curcumin's inhibition of APN is direct and irreversible.

How curcumin binds isn't known, although Kwon modeled a possible scenario. He suspects that the , -unsaturated ketone moieties may covalently link to two nucleophilic amino acids in APN's active site.

Hynda K. Kleinman, a chemist and cell biologist at NIH who studies angiogenesis, says Kwon's finding opens up the possibility of developing more potent APN inhibitors based on the structure of curcumin. And curcumin itself is "an exciting compound because it can be taken orally and may not have any side effects for cancer patients."



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