Prostate cancer is one of the most common cancers in the Western world, and it is believed that an individual's diet affects his risk of developing cancer. There has been an interest in examining phytochemicals, the secondary metabolites of plants, in order to determine their potential anti-cancer activities in vitro and in vivo. In this study we document the effects of proanthocyanidins (PACs) from the American Cranberry (Vaccinium macrocarpon) on matrix metalloproteinase (MMP) activity in DU145 human prostate cancer cells. Cranberry PACs decreased cellular viability of DU145 cells at a concentration of 25 µg/ml by 30% after 6 h of treatment. Treatment of DU145 cells with PACs resulted in an inhibition of both MMPs 2 and 9 activity. PACs increased the expression of TIMP-2, a known inhibitor of MMP activity, and decreased the expression of EMMPRIN, an inducer of MMP expression. PACs decreased the expression of PI-3 kinase and AKT proteins, and increased the phosphorylation of both p38 and ERK1/2. Cranberry PACs also decreased the translocation of the NF-κB p65 protein to the nucleus. Cranberry PACs increased c-jun and decreased c-fos protein levels. These results suggest that cranberry PACs decreases MMP activity through the induction and/or inhibition of specific temporal MMP regulators, and by affecting either the phosphorylation status and/or expression of MAP kinase, PI-3 kinase, NF-κB and AP-1 pathway proteins. This study further demonstrates that cranberry PACs are a strong candidate for further research as novel anti-cancer agents.

Prostate cancer is one of the most common cancers in the world, and its prevalence is expected to increase appreciably in the coming decades. As such, more research is necessary to understand the etiology, progression and possible preventative measures to delay or to stop the development of this disease. Recently, there has been interest in examining the effects of whole extracts from commonly harvested crops on the behaviour and progression of cancer. Here, we describe the effects of whole cranberry extract (WCE) on the behaviour of DU145 human prostate cancer cells in vitro. Following treatment of DU145 human prostate cancer cells with 10, 25 and 50 μg ml⁻¹ of WCE, respectively for 6 h, WCE significantly decreased the cellular viability of DU145 cells. WCE also decreased the proportion of cells in the G2-M phase of the cell cycle and increased the proportion of cells in the G1 phase of the cell cycle following treatment of cells with 25 and 50 μg ml⁻¹ treatment of WCE for 6 h. These alterations in cell cycle were associated with changes in cell cycle regulatory proteins and other cell cycle associated proteins. WCE decreased the expression of CDK4, cyclin A, cyclin B1, cyclin D1 and cyclin E, and increased the expression of p27. Changes in p16(INK4a) and pRBp107 protein expression levels also were evident, however, the changes noted in p16(INK4a) and pRBp107 protein expression levels were not statistically significant. These findings demonstrate that phytochemical extracts from the American cranberry (Vaccinium macrocarpon) can affect the behaviour of human prostate cancer cells in vitro and further support the potential health benefits associated with cranberries.

This study examined the effects of a proanthocyanidin‐enriched fraction (PAC) from cranberry (Vaccinium macrocarpon) on matrix metalloproteinase (MMP) activity in DU145 human prostate cancer cells in vitro. MMP‐2/−9 activity was inhibited by PAC in a dose/time dependent manner. PAC (25 ug/mL) decreased cellular viability 30% post 6 h.of treatment and had no significant effect on cellular viability post 3 h. Treatment of DU145 cells with PAC for 3 h. resulted in increased expression of p‐p38, pERK‐1, pERK‐2 protein levels. Increased JNK1 and decreased JNK2 protein expression occurred in response to PAC with corresponding alterations in p‐JNK1 and p‐JNK2. PAC treatment decreased protein expression levels of AKT, p‐AKT, P‐I‐3 kinase p85/p110 proteins. Treatment of DU145 cells with PAC resulted in inhibition of translocation of NF‐kB as suggested by decreased protein expression of p65 in the nuclear fraction. No apparent change in IkB alpha protein levels were noted. Decreased protein levels of p‐IkB alpha were observed. PAC fraction has the ability to inhibit MMP‐2/−9 activity at a concentration which is not cytotoxic to these cells suggesting that PACs inhibit MMP activity levels in DU145 cells in a targeted manner independent of cellular cytotoxicity effects. (N.C.I.C.‐ Canadian Cancer Society, P.E.I. Health Research Program, The Cranberry Institute (Wisconsin Board) funded)