Proanthocyanidins from the American Cranberry (Vaccinium macrocarpon) inhibit matrix metalloproteinase‐2 and matrix metalloproteinase‐9 activity in human prostate cancer cells via alterations in multiple cellular signalling pathways

Abstract

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.

Cranberry intervention in patients with prostate cancer prior to radical prostatectomy. Clinical, pathological and laboratory findings

“…Studies on the possible effects of cranberry and its components on prostate cancer were realized only in DU 145 human prostate cancer cells which are androgen independent. Treatment of cranberry proanthocyanidinenriched fraction inhibited matrix metalloproteinase-2 and -9 (MMP) activity through the induction and/or inhibition of specific temporal MMP regulators 10 . MMP activity is associated with tumor cell invasion and metastasis.…”

“…These include vitamins C, E, K, organic and phenolic acids, saccharides, flavan-3-ols, flavonols, anthocyanins, anthocyanidins, proanthocyanidins and triterpenoids, shown to possess anti-bacterial, anti-viral, anti-oxidant, anti-inflammatory, anti-angiogenic and anti-cancer activities 8,9 . Most of this evidence, with the exception of preventing urinary tract infections, was derived from studies on prostate cancer cell lines [10][11][12][13] . Our recent clinical study reported that daily intake of 1500 mg cranberry powder for 6 months significantly reduced total prostate-specific antigen (PSA) elevated from chronic non-bacterial prostatitis, and/or benign prostate hyperplasia 14 .…”

Cranberries and Cancer: An Update of Preclinical Studies Evaluating the Cancer Inhibitory Potential of Cranberry and Cranberry Derived Constituents

“…The data presented in this review strongly support the anti-proliferative and pro-death capacities of cranberries in a multitude of cancer cell lines and select in vivo models including xenograft and chemically induced cancer models. The precise cancer inhibitory mechanisms associated with cranberries in specific targets are still be elucidated, but preclinical studies utilizing cranberry proanthocyanidins show inactivation of the PI3K/AKT/mTOR pathways and modulation of MAPK signaling in esophageal, neuroblastoma, ovarian and prostate cancer cells and in esophageal xenografts [39,44,49,52]. Moreover, cranberry proanthocyanidins have recently been shown to induce autophagic markers in vitro and in vivo [39], suggesting an alternative mode of cell death induction and tumor inhibition that requires further evaluation in additional cancer targets.…”

“…Cancer cell lines originating from the oral cavity are susceptible to reduced viability following treatment with cranberry extract (50.0-180.6 µg/mL), cranberry juice extract (150.0 µg/mL) and a total polyphenolic fraction (200.0 µg/mL) with cranberry extract (50.0 µg/mL) treatment of CAL27 cells having the lowest GI 50 [24,33,47]. Ten studies have documented the effectiveness of a cranberry extract, cranberry juice extract, a flavonoid rich extract and cranberry proanthocyanidins at significantly reducing the viability of prostate cancer cells [24][25][26]28,33,36,45,[50][51][52]. The most efficacious constituent appears to be a cranberry proanthocyanidin extract, which inhibits the viability of RWPE-1 and RWPE-2 prostate cancer cell lines with a GI 50 of approximately 6.5 µg/mL [33].…”

Cranberries and Cancer: An Update of Preclinical Studies Evaluating the Cancer Inhibitory Potential of Cranberry and Cranberry Derived Constituents

“…Furthermore, cranberry proanthocyanidins (25.0 µg/mL) increase mitogen-activated protein kinase (MAPK) signaling and decrease PI3K/AKT signaling in prostate cancer cells, suggesting a common cell death mechanism with esophageal adenocarcinoma, ovarian and neuroblastoma cancer cells [52].…”