Anti-leukemia activity of cranberry A-PACS is mediated by disruption of iron metabolism

Some of the health effects of cranberries are associated with a unique class of compounds known as A-type proanthocyanidins (A-PACs). Preliminary studies of the biological effects of A-PACs indicated these activities may be associated with their ability to function as iron chelators. Several studies indicated that iron chelators have anti-tumor activities. This information prompted us to investigate the effects of A-PACs on iron metabolism and leukemia cell survival. Isolation techniques were developed to obtain A-PAC fractions from cranberry cultivars of Vaccinium macrocarpon Ait., or from the cranberry powder CystiCran-40. Phytochemical analysis indicated that the A-PAC fractions consisted mostly of small A-PACs and that CystiCran-40 showed a similar profile as A-PACs, but with additional flavonoids such as quercetin derivatives. The survival and iron metabolism effects of leukemia cells treated with A-PAC fractions or CystiCran-40 were assessed using flow cytometry. A-PAC fractions proved more effective than CystiCran-40at inducing apoptosis, whereas an A-PAC dimer was the least effective. Among the cell lines tested, REH and K562 were the most sensitive while OCI-AML-3 and KG-1 were the most resistant. A-PAC fractions also increased reactive oxygen species and upregulated the transferrin receptor. These results suggest cranberry A-PACs have potential therapeutic value for the treatment of leukemia and that their anti-tumor mechanisms may involve effects on iron metabolism.