Phytochemicals from North American cranberry (Vaccinium macrocarpon) fruit may be expected to influence the development of colon cancer. Tissue-culture models were used to assess effects of cranberry components on cell proliferation, apoptosis, and the formation of tumor cell colonies. Several phytochemicals and fractions isolated from whole cranberry fruit were previously reported to inhibit growth and proliferation of breast, colon, prostate, and other tumor cell lines. In HT-29 and HCT116 colon tumor cell lines, cranberry proanthocyanidins (PACs) and ursolic acid inhibited the formation of tumor colonies over a two week period in a dose-dependent manner. Apoptosis is likely to play a role in limiting tumor cell proliferation. In HT-29 and HCT116 colon tumor cell lines treated with either ursolic acid or a cranberry proanthocyanidin fraction, the percentage of cells undergoing apoptosis increased in a dose-dependent manner. Thus, cranberry phytochemicals have the potential to limit carcinogenesis.

Fruit extracts of four Vaccinium species (lowbush blueberry, bilberry, cranberry, and lingonberry) were screened for anticarcinogenic compounds by a combination of fractionation and in vitro testing of their ability to induce the Phase II xenobiotic detoxification enzyme quinone reductase (QR) and to inhibit the induction of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis, by the tumor promoter phorbol 12-myristate 13-acetate (TPA). The crude extracts, anthocyanin and proanthocyanidin fractions were not highly active in QR induction whereas the ethyl acetate extracts were active QR inducers. The concentrations required to double QR activity (designated CDqr) for the ethyl acetate extracts of lowbush blueberry, cranberry, lingonberry, and bilberry were 4.2, 3.7, 1.3, and 1.0 microgram tannic acid equivalents (TAE), respectively, Further fractionation of the bilberry ethyl acetate extract revealed that the majority of inducer potency was contained in a hexane/chloroform subfraction (CDqr = 0.07 microgram TAE). In contrast to their effects on QR, crude extracts of lowbush blueberry, cranberry, and lingonberry were active inhibitors of ODC activity. The concentrations of these crude extracts needed to inhibit ODC activity by 50% (designated IC50) were 8.0, 7.0, and 9.0 micrograms TAE, respectively. The greatest activity in these extracts appeared to be contained in the polymeric proanthocyanidin fractions of the lowbush blueberry, cranberry, and lingonberry fruits (IC50 = 3.0, 6.0, and 5.0 micrograms TAE, respectively). The anthocyanidin and ethyl acetate extracts of the four Vaccinium species were either inactive or relatively weak inhibitors of ODC activity. Thus, components of the hexane/chloroform fraction of bilberry and of the proanthocyanidin fraction of lowbush blueberry, cranberry, and lingonberry exhibit potential anticarcinogenic activity as evaluated by in vitro screening tests.

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.

AIMS: The aim of the study was to assess whether the oral intake of cranberry juice cocktail compared with apple juice was associated with a significant difference in urinary symptoms experienced during radical external beam radiation therapy (EBRT) for prostate carcinoma.

MATERIALS AND METHODS: One hundred and twelve men with prostate cancer were randomised to either 354 ml cranberry juice or apple juice a day. Stratification was based on a history of a previous transurethral resection of prostate (TURP yes/no) and baseline International Prostate Symptom Score (IPSS 6 or > or = 6) of urinary symptoms.

RESULTS: The maximum IPSS (MRT) and the maximum change in IPSS from baseline (DRT) are used to report the results. We analysed the effects of juice allocation on DRT and MRT using analysis of covariates (ANCOVA). We observed no significant difference for DRT (P = 0.39) or MRT (P = 0.76) related to the consumption of cranberry compared with apple juice. However, we found a significant relationship between the history of a previous TURP and both DRT (P = 0.01) and MRT (P = 0.01). The history of a previous TURP was associated with lower values for both end points. Baseline IPSS was significant for DRT (P = 0.004) and MRT (P or = 0.001). We found a significant relationship between the baseline IPSS 6 or > or = 6 cut point on MRT (P or = 0.001) but not on DRT (P = 0.43). The use of neoadjuvant hormones had no significant effect on DRT (P = 0.64) or MRT (P = 0.76). The use of additional symptomatic medication during the study was not significantly different between the two arms.

CONCLUSIONS: This study shows no significant difference in the urinary symptoms experienced during EBRT related to the consumption of cranberry juice compared with apple juice.

Edible fruits and berries may serve as sources for novel anticancer agents, given that extracts of these foods have demonstrated cytotoxic activity against tumor cell lines. Semipurified, flavonoid-rich extracts of cranberry (Vaccinia macrocarpa) were shown previously to arrest proliferation of tumor cells and induce apoptosis. However, the ability of cranberry flavonoids to inhibit tumor growth in vivo has not been reported other than in a preliminary report. As model systems for testing this activity, human tumor cell lines representative of three malignancies were chosen: glioblastoma multiforme (U87), colon carcinoma (HT-29), and androgen-independent prostate carcinoma (DU145). A flavonoid-rich fraction 6 (Fr6) and a more purified proanthocyanidin (PAC)-rich fraction were isolated from cranberry presscake and whole cranberry, respectively, by column chromatography. Fr6 and PAC each significantly slowed the growth of explant tumors of U87 in vivo, and PAC inhibited growth of HT-29 and DU145 explants (P 0.05), inducing complete regression of two DU145 tumor explants. Flow cytometric analyses of in vitro-treated U87 cells indicated that Fr6 and PAC could arrest cells in G1 phase of the cell cycle (P 0.05) and also induce cell death within 24 to 48 h of exposure (P 0.05). These results indicate the presence of a potential anticancer constituent in the flavonoid-containing fractions from cranberry extracts.

Phytochemicals contribute to the vibrant colors of fruits and it is suggested that the darker the fruit the higher the antioxidative or anticarcinogenic properties. In this study we investigated the possible effects of blueberries (BLU), blackberries (BLK), plums (PLM), mangoes (MAN), pomegranate juice (POJ), watermelon juice (WMJ) and cranberry juice (CBJ) on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in Fisher 344 male rats. Forty-eight male Fisher 344 rats were randomly assigned to eight groups (n=6). The groups were fed AIN-93G as a control (C) diet, the rats fed fruits received AIN-93G+5% fruits and the groups that were given fruits juices received 20% fruit juice instead of water. The rats received subcutaneous injections of AOM at 16 mg/kg body weight at seventh and eighth weeks of age. At 17th week of age, the rats were killed by CO(2) asphyxiation. Total ACF numbers (mean+/-SEM) in the rats fed CON, BLU, BLK, PLM, MNG, POJ, WMJ and CBJ were 171.67+/-5.6, 11.33+/-2.85, 24.0+/-0.58, 33.67+/-0.89, 28.67+/-1.33, 15.67+/-1.86, 24.33+/-3.92 and 39.0+/-15.31. Total glutathione-S-transferase (GST) activity (mICROmol/mg) in the liver of the rats fed fruits (except BLK) and fruit juices were significantly (p<0.05) higher in the rats fed fruits and fruit juices compared with the control. Our findings suggest that among the fruits and fruit juices, BLU and POJ contributed to significant (P<0.05) reductions in the formation of AOM-induced ACF.

Studies employing mainly in vitro tumor models show that extracts and compounds isolated from cranberry fruit (Vaccinium macrocarpon) inhibit the growth and proliferation of several types of tumor including breast, colon, prostate, and lung. Proanthocyanidin oligomers, flavonol and anthocyanin glycosides and triterpenoids are all likely contributors to the observed anticancer properties and may act in a complementary fashion to limit carcinogenesis. Possible chemopreventive mechanisms of action by cranberry phytochemicals include induction of apoptosis in tumor cells, reduced ornithine decarboxylase activity, decreased expression of matrix metalloproteinases associated with prostate tumor metastasis, and anti-inflammatory activities including inhibition of cyclooxygenases. A review of recent studies suggests a potential role for cranberry as a dietary chemopreventive and provides direction for future research.

This article reviews the existing research on the anticancer properties of cranberry fruit and key phytochemicals that are likely contributors to chemoprevention. Results from in vitro studies using a variety of tumor models show that polyphenolic extracts from Vaccinium macrocarpon inhibit the growth and proliferation of breast, colon, prostate, lung, and other tumors, as do flavonols, proanthocyanidin oligomers, and triterpenoids isolated from the fruit. The unique combination of phytochemicals found in cranberry fruit may produce synergistic health benefits. Possible chemopreventive mechanisms of action by cranberry phytochemicals include induction of apoptosis in tumor cells, reduced ornithine decarboxylase activity, decreased expression of matrix metalloproteinases associated with prostate tumor metastasis, and antiinflammatory activities including inhibition of cyclooxygenases. These findings suggest a potential role for cranberry as a dietary chemopreventive and provide direction for future research.

In addition to its nutritional value, cranberry juice has been effective in treating urinary tract infections. Various reports have also demonstrated its potential for inhibiting in vitro growth of transformed cell lines. Here we show that a fraction [nondialyzable material (NDM) of a molecular weight range 12,000-30,000 (NDM 12-30K)] derived from cranberry juice impairs in vitro growth and invasion through extracellular matrix of Rev-2-T-6 murine lymphoma cells. Furthermore, intraperitoneal injection of this fraction at nontoxic doses both inhibits the growth of Rev-2-T-6 tumors in vivo and enhances the generation of antilymphoma antibodies. These findings demonstrate the in vivo efficacy of cranberry components against malignant lymphoma in immune competent hosts.

The occurrence of esophageal adenocarcinoma and its only recognized precursor lesion, Barrett's esophagus, has rapidly increased during the past three decades. The precise reason for the rise remains to be elucidated, but increasing rates have been linked to multiple nutritional factors. Plant-based diets have generally been associated with a reduction of risk for esophageal adenocarcinoma and those of animal origin with risk escalation. Moreover, a number of recent in vitro and limited in vivo investigations have reported that cranberry extracts affect multiple cancer-associated processes in breast, colon, prostate, and other cancer cell lines of epithelial origin. Thus, this study sought to investigate the chemopreventive potential of a cranberry proanthocyanidin rich extract (PAC) in SEG-1 human esophageal adenocarcinoma (EAC) cells. PAC pretreatment significantly inhibited the viability and proliferation of EAC cells in a time- and dose-dependent manner. Moreover, PAC (50 microg/mL) significantly inhibited acid-induced cell proliferation of SEG-1 cells. PAC treatment induced cell cycle arrest at the G1 checkpoint and significantly reduced the percentage of SEG-1 cells in S-phase following 24 and 48 h of exposure. PAC treatment also resulted in significant induction of apoptosis. Thus, PAC modulates cell cycle regulation, aberrant proliferation, and apoptosis, all key biological processes altered during progression to esophageal adenocarcinoma. These findings support that further mechanistic studies are warranted to more fully elucidate the inhibitory potential of PAC against esophageal cancer.