Cranberry Metabolites that Inhibit Growth of Human Bladder Cancer Cells

Cranberry (Vaccinium macrocarpon Ait. Ericaceae), a native fruit of North America, has attracted much public interest because of its potential beneficial health effects, including cancer prevention. Our previous studies have shown that cranberry extract can inhibit chemically-induced bladder tumorigenesis [1]. To test our hypothesis that cranberry juice is an effective cancer chemopreventive agent for human bladder cancer, the anti-proliferative activities of number of cranberry metabolites were evaluated using a panel of human bladder cancer cell lines (RT4, SCABER, SV-HUC1, and SW-780). Among 17 compounds tested, quercetin 3-O-glucoside and 3'-O-methylquercetin showed strong concentration-dependent tumor cell growth inhibitory activities with IC₅₀ values in a range of 8–43? M. Furthermore, 3'-O-methylquercetin revealed very low inhibitory activity in normal human uroepithelial cells (HUC) compared to bladder cancer cells, indicating that its cytotoxic activity is specific for cancer cells but not to the normal cells. A high-content image-based analysis of the cell cycle distribution following treatment with the test compounds was performed and quercetin and 3'-O-methylquercetin caused G2 cell cycle arrest and apoptosis. To determine whether the differenzial cell growth inhibitory effects of isomeric quercetin 3-O-glucoside (active) and quercetin 3-O-galactoside (inactive) are related to their metabolism by the cancer cells, SW-780 cells were incubated with these compounds and their metabolism was examined by LC-MS/MS. Compared to quercetin 3-O-glucoside, quercetin 3-O-galactoside undergoes very little metabolism. These data suggest that the methylated metabolite may be the active form of quercetin in bladder cancer cells and emphasize the importance of cranberry metabolites in the bladder cancer chemoprevention.

Acknowledgements : These studies were supported by NIH (R21CA137519–01 (JP, PI). We would also like to thank UAB Targeted Metabolomics and Proteomics Laboratory for mass spectrometric analyses. Reference: (1) Prasain JK, Jones K, et al. (2008) Oncology Reports 19: 1565–1570.