Chemopreventive efficacy of oral curcumin: a prodrug hypothesis

Oral consumption of curcumin, a natural polyphenol, is associated with reduced incidence of cancer. Yet, a significant amount of the orally dosed compound is eliminated in the feces, and a major fraction of the absorbed compound is metabolized to inactive glucuronides, resulting in poor bioavailability (<1%). It is not known how oral curcumin exhibits chemopreventive activity. We propose curcumin glucuronide is an inflammation-responsive natural prodrug that is converted back to curcumin on demand at the site of action. Our studies show elevated levels of β-glucuronidase, an enzyme that hydrolyzes the glycosidic bond of glucuronides to generate the parent compound, in human breast cancer. Oral administration of curcumin in mouse tumor models generated significant tumor levels of the polyphenol. Intravenous administration of the glucuronide resulted in the formation of curcumin in the tumor tissue. Chronic daily oral curcumin dosing led to tumor accumulation of curcumin and inhibition of tumor growth in tu...