Compounds of Vaccinium macrocarpon inhibit DU145 human prostate cancer cells

Prostate cancer is the second most prevalent cancer in North American males. A series of in vitro studies were conducted to examine the effect of compounds from the American cranberry (Vaccinium macrocarpon) on the behavior of DU145 human prostate cancer cells. These compounds (Proanthocyanidin [Pacs], Flavonol [Flays], Ursolic acid [UA]) were hypothesized to be the principle contributors to previous research where V. macrocarpon treatment of DU145 cells was found to induce apoptosis and changes in matrix metalloproteinase (MMP) activity. Pacs treatment of DU145 cells induced apoptosis by up-regulating the protein expression of intrinsic pro-apoptotic proteins culminating in induction of the final stages of apoptosis, poly ADP-ribose protein (PARP) cleavage and nucleosome formation. Flay treatment of DU145 human prostate cells also induces apoptosis through the intrinsic pathway. These inductions led to cytochrome c induction leading to DNA cleavage, but without the PARP cleavage normally present in apoptosis induction. UA, a compound found in the skin of cranberries, was studied for its ability to induce changes in the activity of MMPs released from DU 145 cells. UA inhibited the activity of MMP-9, Pro-MMP-2 and MMP-2. UA treatment of DU145 cells induces the expression of tissue inhibitor of matrix metalloproteinases -1/-2 (TIMP-1/-2). Extracellular matrix metalloproteinase protein inducer (EMMPRIN) and reversion inducing cysteine rich protein with kazal motifs (RECK), two regulators of MMP activity, were both inhibited by UA treatment of DU145 cells. Cell signaling pathways associated with the regulation of MMP activity by UA were also evaluated. It was observed that the effect of UA was mediated through a MAPK and NF-κB dependent manner. These results suggest that V. macrocarpon is a viable and important source of anti-cancer compounds.