The effect of cranberry extracts and juices during cranberry juice processing on the antiproliferative properties against colon cancer cells was investigated. Two colon cancer cell lines HT-29 and LS-513 were treated with different concentrations of cranberry phenolic extracts from fruits, puree, depectinised puree and pomace and different concentration of three juices (raw, filtered and concentrated juices). The phenolic extracts consisted of water-soluble phenolic compounds, apolar phenolic compounds and anthocyanins. These phenolic extracts and juices were tested against two cell lines at pH 2.5 (natural
juice pH) and at pH 7.0 (physiological pH). All cranberry extracts and juices could inhibit the growth of both cell lines with the IC50 values (the concentration of phenolic content required to inhibit 50% the growth of cancer cells) varied from 3.8 to 179.2 lg gallic acid equivalent/ml. It was found that three types of extracts from fruit at pH 7.0 were the most effective at inhibiting the growth of HT-29 cell line. Extracts containing anthocyanins from fruit and from pomace were the most and the least efficient, respectively, in inhibiting the growth of both cancer cell lines. Further, three juices at natural pH (pH 2.5) were more effective at inhibiting the growth of two cell lines as compared to juices at pH 7.0. Concentrated juice at both pH values was the most effective at growth inhibition of two cancer cell lines compared to two other juices.

Cranberry extracts may provide beneficial health effects in the treatment of various diseases, including cancer. However, the underlying molecular mechanisms of antineoplastic properties are not understood. We report the effect of a proanthocyanidin (PAC)-rich isolate from cranberry (PAC-1) as a therapeutic agent with dual activity to target both ovarian cancer viability and angiogenesis in vitro. PAC-1 treatment of chemotherapy-resistant SKOV-3 cells blocked cell cycle progression through the G2/M phase, increased the generation of reactive oxygen species (ROS), and induced apoptosis through activation of intrinsic and extrinsic pathway components. Cytotoxicity of PAC-1 was partially based on ROS generation and could be blocked by co-treatment with antioxidant glutathione. PAC-1 reduced the cell viability of both SKOV-3 ovarian cancer cells and HUVEC endothelial cells in a dose-dependent manner and blocked the activation of the pro-survival factor AKT. Furthermore, PAC-1 blocked vascular endothelial growth factor (VEGF)-stimulated receptor phosphorylation in endothelial cells, which correlated with the inhibition of endothelial tube formation in vitro. Our findings suggest that PAC-1 exerts potent anticancer and anti-angiogenic properties and that highly purified PAC from cranberry can be further developed to treat ovarian cancer in combinational or single-agent therapy.

Optimized purification of oligomeric proanthocyanidines (PAC) from cranberry generated PAC-1A which selectively affected the viability of various neuroblastoma (NB) cell lines representing a spectrum of high-risk NB features. PAC-1A caused a loss of mitochondrial transmembrane depolarization potential (∆Ψm) and increased generation of reactive oxygen species (ROS) which was directly correlated to the modulation of apoptotic marker proteins in SMS-KCNR cells. PAC-1A reduced the expression of pro-survival (Bcl-2, MCL-1, Bcl-xL) and increased levels of pro-apoptotic (Bax, Bad, Bid) Bcl family proteins, upregulated the activity of SAPK/JNK MAPK and downregulated expression or activity of PI3K/AKT/mTOR pathway components. PAC-1A increased the cellular uptake/retention of cyclophosphamide (CP). PAC-1A and CP synergistically increased cytotoxicity and expression of pro-apoptotic markers, reduced cellular glutathione (GSH) and superoxide dismutase (SOD) levels. Additional features of PAC-1A as an anticancer drug as shown in SMS-KCNR NB cells include delay of cell cycle progression and induction of cell death via TNF-family death receptor activity, thus, targeting both the extrinsic and intrinsic pathway of apoptosis. PAC-1A partially blocked the cell cycle in G2/M phase which correlated with a decrease of the G0/G1 subpopulation, upregulation of cyclin D1 and downregulation of CDK6 and p27 expression. In summary, PAC-1A has demonstrated chemotherapeutic potential to treat a broad spectrum of NBs including highly malignant tumors that show resistance to standard chemotherapeutics and apoptotic stimuli.

Abstract:Proanthocyanidin-rich extracts were prepared by fractionation of the fruit of theNorthAmerican cranberry (Vaccinium macrocarpon). In vitro growth inhibition assays in eight tumor cell lines showed that selected fractions inhibited the growth of H460 lung tumors, HT-29 colon and K562 leukemia cells at GI50 values ranging from 20 to 80 μgml−1. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) of one of these fractions found it to be composed of polyflavan-3-ols, which are primarily tetramers through heptamers of epicatechin containing one or two A-type linkages. Whole cranberry extract and the proanthocyanidin fractions were screened for effect on the expression of matrix metalloproteinases in DU 145 prostate carcinoma cells. The expression of MMP-2 and MMP-9 was inhibited in response to whole cranberry extract and to a lesser degree by the proanthocyanidin fractions

The present study investigated the effect of cranberries on development of colon tumors induced by azoxymethane in Fisher 344 male rats. Fifty five rats were divided into five groups and fed with control (AIN 93) or treatment diets: cranberry meal (5, 10%) cranberry juice (2.5, 5%). Two AOM (16 mg kg-1 b.wt.) injections were given weekly for 2 weeks for induction of colon tumors. At 45 weeks of age, all rats were killed and colons were evaluated for tumor incidence, size of tumor and tumor multiplicity. Selected hepatic phase 1 (CYP2E1), phase 11 (GST) and antioxidative enzyme (catalase and SOD) activities were determined. Tumor size and tumors/tumor bearing rat were higher (p<=0.05) in the control group. Number of tumors was lower in cranberry fed rats compared to control. Administration of cranberry to rats increased (p<0.05) hepatic enzyme activities by 1.2-3.7 fold compared to control fed rats. These results indicate that feeding cranberry (meal and juice) inhibited colon tumors induced by AOM and enhanced the activity of hepatic enzymes.

Abstract. Background: Traditional Botanical Supplement-
101 (TBS-101) is a newly developed proprietary botanical
agent containing seven standardized botanical extracts,
including: Panax ginseng, cranberry, green tea, grape skin,
grape seed, Ganoderma lucidum and chamomile. Each of the components has been consumed either in the regular diet or as natural supplement. When used as a single agent, each of these seven botanicals has been implicated in
chemoprevention and therapy in various types of cancer. The anticancer effect of TBS-101, with the specific combination of these anti-cancer botanicals for the treatment of prostate cancer (PCa), has not been tested. Materials and Methods: The IC50 and the effect of TBS-101 on the proliferation and apoptosis of PC-3 cells were determined. Tumor xenograft mice were generated by subcutaneously implanting PC-3 cells into mice and tumors were allowed to grow to different sizes before starting the treatment. The effects of TBS-101 on tumor growth were assessed by measuring tumor size and by histological, pathological and immunohistochemical analyses. A basic toxicity study was performed to test the tolerance of the mice to high doses of TBS-101. Results: Treatment of the PC-3 cells with TBS-101 resulted in a dosedependent
inhibition of cell growth, with an IC50 of 1.4 μg/ml. A concomitant induction of apoptosis in PC-3 cells
treated with TBS-101 was also observed. Upon the treatment with TBS-101, all three groups of mice bearing moderate or large tumors showed significant inhibition of tumor growth and invasion. In contrast, control mice treated with vehicle alone had significant tumor growth and lymph node metastasis. In the basic toxicity studies, high doses of TBS- 101 exerted no toxicity in healthy or tumor-bearing mice. Conclusion: The natural botanical agent TBS-101 has a good safety profile and significant anticancer activities in hormone-refractory PC-3 cells and large aggressive PC-3 tumors in a xenograft mouse model and has great potential for the treatment of aggressive prostate cancer

In this study, the chemopreventive potential of Cranberry was analyzed in reducing the Aberrant Crypt Foci (ACF) induced by Azoxymethane (AOM) in Fisher 344 male rats. After 1 week period of acclimatization, rats were divided into five different groups. Cranberry meal was mixed in an AIN 93G based diet at 5 and 10% and juice was provided at 2.5 and 5%. Daily feed intake and weekly body weights were recorded. At 17 week of age, rats were killed and samples were collected. Number of ACF and number of crypts/foci were enumerated in the colon. There were no significant differences in feed intake, weight gain, cecal weight and cecal pH among all groups. Total ACF incidence (119) was significantly (p<0.05) higher in control group than in treatment groups. Reduction in total ACF induction was higher in rats fed 10% Cranberry (65.75%) compared to control. A two to six fold increase in selected hepatic enzymes activities (units/mg enzyme) were seen in rats fed 5 and 10% treatment diets compared to control. Results of this study showed that administration of Cranberry meal and juice resulted in significant (p<0.05) reductions in the incidence of ACF in azoxymethane induced preneoplastic lesions.

BACKGROUND: Cranberry (Vaccinium marcocarpon) fruit and quercetin, a major flavonoid found in cranberries, are likely contributors to chemoprevention, and their anti-inflammatory activities may play a potential role in colon cancer prevention. The aim of this study was to examine the effect of cranberry extract and quercetin on basal expression of cyclooxygenase-2 (COX-2) and IκBα as well as the effect on phorbol 12-myristate 13-acetate (PMA)-induced COX-2 expression in colon cancer cells.
RESULTS: HT-29 human colon adenocarcinoma cells were treated with various concentrations of cranberry extract or quercetin and/or PMA, and the protein expression of COX-2 and IκBα was determined. The results indicated that cranberry extract and quercetin decreased COX-2 expression and suppressed degradation of IκBα in unstimulated cells. In PMA-stimulated cells, cranberry extract was also able to decrease COX-2 expression and suppress degradation of IκBα.
CONCLUSION: The results suggest that a possible mechanism involved in the anti-cancer activity of cranberry and quercetin is partly mediated through its anti-inflammatory action. These findings indicate that cranberry and quercetin may reduce the risk of colon cancer possibly by suppressing inflammatory responses.

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.