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Oncology/Anti-Cancer

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Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells

Posted: 
January 14, 2012
Authors: 
Singh AP, Lange TS, Kim KK, Brard L, Horan T, Moore RG, Vorsa N, Singh RK.
Journal: 
Int J Oncol 40(1):99-108
Abstract: 

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.

MALDI-TOF MS characterization of proanthocyanidins from cranberry fruit (Vaccinium macrocarpon) that inhibit tumor cell growth and matrix metalloproteinase expression in vitro.

Posted: 
January 11, 2011
Authors: 
Neto CC, Krueger CG, Lamoureaux TL, Kondo M, Vaisberg AJ, Hurta RAR, Curtis S, et al
Journal: 
J Sci Food Agr 86(1):18-25
Abstract: 

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

Suppression of colon cancer development in an azoxymethane-fisher 344 rat model by cranberry

Posted: 
January 11, 2011
Authors: 
Sunkara R, Verghese M, Walker LT, Shackelford L
Journal: 
Res J Phytochem 3(2):25-34
Abstract: 

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.

The effect of a novel botanical agent TBS-101 on invasive prostate cancer in animal models

Posted: 
January 11, 2011
Authors: 
Evans S, Dizeyi N, Abrahamsson PA and Persson J
Journal: 
Anticancer Res 29(10):3917-24
Abstract: 

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

Chemopreventive potential of cranberries on azoxymethane induced aberrant crypt foci in Fisher 344 male rats

Posted: 
December 17, 2010
Authors: 
Sunkara R, Verghese M, Panala V, Field R, Boateng J, Shackelford L. A. and Walker, L. T.
Journal: 
Int J Canc Res 4 (2):52-60
Abstract: 

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.

Cranberry extract and quercetin modulate the expression of cyclooxygenase-2 (COX-2) and I kappa B alpha in human colon cancer cells

Posted: 
December 16, 2010
Authors: 
Narayansingh R, Hurta RAR
Journal: 
J Sci Food Agr 89(3):542-547
Abstract: 

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.

Cranberry PACs and triterpenoids: anti-cancer activities in colon tumor cell lines

Posted: 
November 17, 2010
Authors: 
Liberty AM, Amoroso JW, Neto CC, Hart PE, Patil B, Murano P, Amiot-Carlin MJ
Journal: 
Acta Hort 841:61-66
Abstract: 

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.

In vitro anticancer activity of fruit extracts from Vaccinium species

Posted: 
November 17, 2010
Authors: 
Bomser J, Madhavi DL, Singletary K, Smith MA
Journal: 
Planta Med 62(3):212-6
Abstract: 

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.

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.

Posted: 
November 17, 2010
Authors: 
Déziel BA, Patel K, Neto C, Gottschall-Pass K, Hurta RA
Journal: 
J Cell Biochem 111(3):742-54
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.

A randomised trial of cranberry versus apple juice in the management of urinary symptoms during external beam radiation therapy for prostate cancer

Posted: 
November 13, 2010
Authors: 
Campbell G, Pickles T, D'yachkova Y
Journal: 
Clin Oncol (R Coll Radiol) 15(6):322-8
Abstract: 

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 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 = 6 cut point on MRT (P

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.

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