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Anticancer Activity of Chlorhexidine and Cranberry Extract: an In-Vitro Study.

Posted: September 4, 2018
Authors: Khairnar MR; Wadgave U; Jadhav H; Naik R.
Journal: Journal of Experimental Therapeutics & Oncology. 12(3):201-205

Abstract: Introduction: Oral cancer is considered to be a global pandemic. The study was conducted to assess the anti-cancer activities of Chlorhexidine (CHX) and Cranberry against oral cancer cell lines. Material and Methods: Anticancer activity of CHX and Cranberry extract (CE) was assessed against AW13516 (poorly to moderately differentiated squamous cell carcinoma of tongue) and KB (Nasopharyngeal carcinoma) using Sulforhodamine B (SRB) assay at the Advanced Centre for Treatment Research and Education in Cancer (ACTREC) Mumbai, India. Three dose related parameters GI50, TGI and LC50 were calculated for each drug. Results: CE (80micro g/ml) showed no anti-cancer property against AW13516 cell line; however it showed 70.6% growth inhibition against KB cell line. CHX demonstrated 80.15% & 95.7% of growth inhibition against AW13516 & KB cell line respectively. Both the drugs were less potential than positive control drug Adriamycin, as reflected by their GI50, TGI and LC50 values. Conclusion: CHX exhibited better anti-cancer properties than CE for both the oral cancer cell lines.

Dietary Feeding of Freeze-Dried Whole Cranberry Inhibits Intestinal Tumor Development in Apcmin/+ Mice.

Posted: April 4, 2018
Authors: Jin D; Liu T; Dong W; Zhang Y; Wang S; Xie R; Wang B; Cao H.
Journal: Oncotarget. 8(58):97787-97800

Abstract: It is increasingly perceived that dietary components have been linked with the prevention of intestinal cancer. Cranberry is a rich source of phenolic constituents and non-digestible fermentable dietary fiber, which shows anti-proliferation effect in colorectal cancer cells. Herein, we investigated the efficacy of long-term cranberry diet on intestinal adenoma formation in Apcmin/+ mice. Apcmin/+ mice were fed a basal diet or a diet containing 20% (w/w) freeze-dried whole cranberry powder for 12 weeks, and the number and size of tumors were recorded after sacrifice. Our results showed that cranberry strongly prevented the growth of intestinal tumors by 33.1%. Decreased cell proliferation and increased apoptosis were observed in tumors of cranberry-fed mice. Cranberry diet reduced the expression profile of colonic inflammatory cytokines (IFN-gamma, IL-1beta and TNF-alpha) accompanied with increased levels of anti-inflammatory cytokines (IL-4 and IL-10). Moreover, the number of colonic goblet cells and MUC2 production were increased, and the intestinal barrier function was also improved. In addition, cranberry diet increased caecal short chain fatty acids concentrations, and down-regulated epidermal growth factor receptor signaling pathway. These data firstly show the efficacy and associated mechanisms of cranberry diet on intestinal tumor growth in Apcmin/+ mice, suggesting its chemopreventive potential against intestinal cancer.

Evidence of Some Natural Products with Antigenotoxic Effects. Part 1: Fruits and Polysaccharides

Posted: August 15, 2017
Authors: Evidence of Some Natural Products with Antigenotoxic Effects. Part 1: Fruits and Polysaccharides
Journal: Nutrients 9(2)

Abstract: Cancer is one of the leading causes of deaths worldwide. The agents capable of causing damage to genetic material are known as genotoxins and, according to their mode of action, are classified into mutagens, carcinogens or teratogens. Genotoxins are involved in the pathogenesis of several chronic degenerative diseases including hepatic, neurodegenerative and cardiovascular disorders, diabetes, arthritis, cancer, chronic inflammation and ageing. In recent decades, researchers have found novel bioactive phytocompounds able to counteract the effects of physical and chemical mutagens. Several studies have shown potential antigenotoxicity in a variety of fruits. In this review (Part 1), we present an overview of research conducted on some fruits (grapefruit, cranberries, pomegranate, guava, pineapple, and mango) which are frequentl consumed by humans, as well as the analysis of some phytochemicals extracted from fruits and yeasts which have demonstrated antigenotoxic capacity in various tests, including the Ames assay, sister chromatid exchange, chromosomal aberrations, micronucleus and comet assay.

Cranberry Extract as a Supplemented Food inTreatment of Oxidative Stress and Breast Cancer Induced by n-methyl-n-nitrosourea in Female Virgin Rats

Posted: March 6, 2017
Authors: Boshra SA, Hussein MA
Journal: Int J Phytomed 8(2):217-27

Abstract: Breast cancer is the most common cancer and a major cause of death in women. The present study was designed to evaluate the antioxidant and anticancer potential of cranberry extract against N-methyl-N-nitrosourea (MNU) induced mammary carcinoma in rats. The tumor was induced in Female virgin rats of age 50 days by single dose of MNU (50mg/kg.b.w i.p.). After 85 days; all rats developed at least one tumor. Animals were treated with cranberry extract (400 and 600 mg/kg.b.w.orally) and tamoxifen (2mg/kg.b.w. i.p) for 4 weeks (from day 86 to day 113). MNU treatment resulted in a significant decrease (p < 0.05) in blood hemoglobin (Hb), red blood cells (RBC), platelets (PLTs) as well as blood, liver and breast catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD). However, MNU treatment resulted in a significant increase in White blood cells (WBC) as well as plasma, liver and mammary tissue gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), hexosamine, sialic acid and thiobarbituric acid reactive substances (TBARs). Upon administration of the cranberry extract, the levels of WBC, GGT, LDH, hexosamine, sialic acid, TBARs, Hb, RBC, PLTs, CAT, GPx and SOD were significantly normalized. Histopathological changes also confirmed the formation of tumor tubules and neovascularization after the MNU treatment. Cranberry extract administration significantly reduces the growth of MNU-induced mammary tumors, and therefore has strong potential as a useful therapeutic regimen for inhibiting breast cancer development. Comparing the beneficial effect of cranberry extract with that of MNU-induced breast cancer, cranberry extract showed antitumor and antioxidant activity indicated by the measured biochemical parameters and the histopathological examination of mammary tissue. The results of the present study indicate that cranberry extract possesses strong anticancer effects through its role in modulating glycoprotein components and the levels of oxidative stress biomarkers. Cranberry exerted a stronger anticancer effect at the dosage of 600 mg/kg body weight than at dosage 400 mg/kg body weight.

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

Posted: March 1, 2017
Authors: Weh KM, Clarke J, Kresty LA
Journal: Antioxidants 5(3):27

Abstract: Cranberries are rich in bioactive constituents reported to influence a variety of health benefits, ranging from improved immune function and decreased infections to reduced cardiovascular disease and more recently cancer inhibition. A review of cranberry research targeting cancer revealed positive effects of cranberries or cranberry derived constituents against 17 different cancers utilizing a variety of in vitro techniques, whereas in vivo studies supported the inhibitory action of cranberries toward cancers of the esophagus, stomach, colon, bladder, prostate, glioblastoma and lymphoma. Mechanisms of cranberry-linked cancer inhibition include cellular death induction via apoptosis, necrosis and autophagy; reduction of cellular proliferation; alterations in reactive oxygen species; and modification of cytokine and signal transduction pathways. Given the emerging positive preclinical effects of cranberries, future clinical directions targeting cancer or premalignancy in high risk cohorts should be considered.

Cranberry Intervention in Patients with Prostate Cancer Prior to Radical Prostatectomy. Clinical, Pathological, and Laboratory Findings

Posted: March 1, 2017
Authors: Student V, Vidlar A, Bouchal J, Vrbkova J, Kolar Z, Kral M, Kosina P, Vostalova J
Journal: Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 160(4):559-565

Abstract: Background and Objectives. Recently, we described an inverse association between cranberry supplementation and serum prostate specific antigen (PSA) in patients with negative biopsy for prostate cancer (PCa) and chronic nonbacterial prostatitis. This double blind placebo controlled study evaluates the effects of cranberry consumption on PSA values and other markers in men with PCa before radical prostatectomy. Methods: Prior to surgery, 64 patients with prostate cancer were randomized to a cranberry or placebo group. The cranberry group (n=32) received a mean 30 days of 1500 mg cranberry fruit powder. The control group (n=32) took a similar amount of placebo. Selected blood/urine markers as well as free and total phenolics in urine were measured at baseline and on the day of surgery in both groups. Prostate tissue markers were evaluated after surgery. Results: The serum PSA significantly decreased by 22.5% in the cranberry arm (n=31, P<0.05). A trend to down-regulation of urinary beta-microseminoprotein (MSMB) and serum gamma-glutamyltranspeptidase, as well as upregulation of IGF-1 was found after cranberry supplementation. There were no changes in prostate tissue markers or, composition and concentration of phenolics in urine. Conclusions: Daily consumption of a powdered cranberry fruit lowered serum PSA in patients with prostate cancer. The whole fruit contains constituents that may regulate the expression of androgen-responsive genes.

Metabolism and Growth Inhibitory Activity of Cranberry Derived Flavonoids in Bladder Cancer Cells

Posted: March 1, 2017
Authors: Prasain JK, Rajbhandari R, Keeton AB, Piazza GA, Barnes S
Journal: Food Funct 7(9):4012-4019

Abstract: In the present study, anti-proliferative activities of cranberry derived flavonoids and some of their in vivo metabolites were evaluated using a panel of human bladder tumor cell lines (RT4, SCABER, and SW-780) and non-tumorigenic immortalized human uroepithelial cells (SV-HUC). Among the compounds tested, quercetin 3-O-glucoside, isorhamnetin (3'-O-methylquercetin), myricetin and quercetin showed strong concentration-dependent cell growth inhibitory activities in bladder cancer cells with IC50 values in a range of 8-92 micro M. Furthermore, isorhamnetin and myricetin had very low inhibitory activity against SV-HUC even at very high concentrations (>200 micro M) compared to bladder cancer cells, indicating that their cytotoxicity is selective for cancer cells. To determine whether the differential cell growth inhibitory effects of isomeric flavonoids quercetin 3-O-glucoside (active) and hyperoside (quercetin 3-O-galactoside) (inactive) are related to their metabolism by the cancer cells, SW-780 cells were incubated with these compounds and their metabolism was examined by LC-MS/MS. Compared to quercetin 3-O-glucoside, hyperoside undergoes relatively less metabolic biotransformation (methylation, glucuronidation and quinone formation). These data suggest that isorhamnetin and quercetin 3-O-glucoside may be the active forms of quercetin in prevention of bladder cancer in vivo and emphasize the importance of metabolism for the prevention of bladder cancer by diets rich in cranberries.

Anti-leukopenic and antioxidant effects of cranberry extract in benzene and fluorouracil induced leukopenia in rats

Posted: August 22, 2016
Authors: Hussein M.A., Boshra S.A.
Journal: International Journal of Applied Research in Natural Products. 9 (1) (pp 1-8), 2016

Abstract: The present study was to evaluate anti-leukopenia and antioxidant effects of cranberry extract(222mg/kg.b.w, orally)in 400mg/kg.b.w., orally benzene and/or 20mg/kg.b.w., I.P 5-Flourouracil-induced leukopenia rats. Two weeks after induction of leukopenia in rats, cranberry extract was administrated for 30 consecutive days. Onthe31thday, the rats were sacrificed for the estimation of hemoglobin (Hb%), complete blood cell count Leucocyte (WBC) and platelet count (PLT),as well as biochemical parameters; alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), lipid peroxides (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), total cholesterol (TC), triglycerides (TG), HDL-C, LDL-C, p53gene expression, nitric oxide (NO) and tumor necroses factor-alpha (TNF-alpha). The results of this study showed that administration of cranberry extract to leukopenia induced rats demonstrated a significant (P<0.01) increase in Hb%, WBCs and PLT as well as a significant (P<0.01) improvement in biochemical parameters and life span as compared to benzene and/or 5-Flourouracil control rats. The histological examinations of this study revealed damage and degeneration in the lung of benzene and/or 5-Flourouracil treated rats. Also, lung of cranberry treated rats showed significant improvement and protection against benzene and/or 5-Flourouracil harmful effect. On the other hand, the results clearly suggested that the oxidative stress of benzene was higher than 5-Flourouracil. Industrial relevance. Our observations have clearly demonstrated that the cranberry extract has significant antioxidant and anti-leukopenia activity due to presence of phenolic compounds. Cranberry extract possessed a capability to inhibit the lipid peroxidation and activate the antioxidant markers (GSH, SOD and CAT) in leukopenia-induced by 5-Flourouracil and benzene in rats. Also, industrial relevance of the present results showed that cranberry extract can be used as an antioxidant and anti-leukopenia therapeutic agent and deserves clinical trial in the near future as an adjuvant therapy in leukopenic patients. This could serve as a stepping stone towards the discovery of newer safe and effective antitumor agents.

Cranberry Proanthocyanidins Inhibit Esophageal Adenocarcinoma In Vitro and In Vivo Through Pleiotropic Cell Death Induction and PI3K/AKT/mTOR Inactivation.

Posted: March 23, 2016
Authors: Kresty LA, Weh KM, Zeyzus-Johns B, Perez LN, Howell AB
Journal: Oncotarget 6(32):33438-55

Abstract: Cranberries are rich in bioactive constituents known to improve urinary tract health and more recent evidence supports cranberries possess cancer inhibitory properties. However, mechanisms of cancer inhibition by cranberries remain to be elucidated, particularly in vivo. Properties of a purified cranberry-derived proanthocyanidin extract (C-PAC) were investigated utilizing acid-sensitive and acid-resistant human esophageal adenocarcinoma (EAC) cell lines and esophageal tumor xenografts in athymic NU/NU mice. C-PAC induced caspase-independent cell death mainly via autophagy and low levels of apoptosis in acid-sensitive JHAD1 and OE33 cells, but resulted in cellular necrosis in acid-resistant OE19 cells. Similarly, C-PAC induced necrosis in JHAD1 cells pushed to acid-resistance via repeated exposures to an acidified bile cocktail. C-PAC associated cell death involved PI3K/AKT/mTOR inactivation, pro-apoptotic protein induction (BAX, BAK1, deamidated BCL-xL, Cytochrome C, PARP), modulation of MAPKs (P-P38/P-JNK) and G2-M cell cycle arrest in vitro. Importantly, oral delivery of C-PAC significantly inhibited OE19 tumor xenograft growth via modulation of AKT/mTOR/MAPK signaling and induction of the autophagic form of LC3B supporting in vivo efficacy against EAC for the first time. C-PAC is a potent inducer of EAC cell death and is efficacious in vivo at non-toxic behaviorally achievable concentrations, holding promise for preventive or therapeutic interventions in cohorts at increased risk for EAC, a rapidly rising and extremely deadly malignancy.

Cranberry extract suppresses interleukin-8 secretion from stomach cells stimulated by Helicobacter pylori in every clinically separated strain but inhibits growth in part of the strains.

Posted: February 15, 2014
Authors: Matsushima M, Suzuki T, Masui A, Mine T, Takagi A
Journal: J Funct Foods 5(2):729-735

Abstract: It is known that cranberry inhibits the growth of Helicobacter pylori (HP). In human stomach, HP basically induces chronic inflammation by stimulating stomach cells to secrete interleukin (IL)-8 and other inflammatory cytokines, and causes stomach cancer, etc. The aim of this study was to investigate the inhibiting effects of cranberry on HP growth and IL-8 secretion from stomach cells induced by HP, using clinically separated HP strains. HP growth in liquid culture and on-plate culture was evaluated by titration after 2-day incubation and by agar dilution technique, respectively. For IL-8 experiments, MKN-45, a stomach cancer cell line, was incubated with HP for 24 h and IL-8 in the medium was assayed by ELISA. Cranberry suppressed growth of the bacteria only in six of the 27 strains. Meanwhile, it suppressed IL-8 secretion in all the strains. The results may suggest a possible role of cranberry in prevention of stomach cancer by reducing gastric inflammation.

Cranberry extract suppresses interleukin-8 secretion from stomach cells stimulated by Helicobacter pylori in every clinically separated strain but inhibits growth in part of the strains

Posted: September 15, 2013
Authors: Matsushima M, Suzuki T, Masui A, Mine T, Takagi A
Journal: J Funct Food 5(2):729–35

Abstract: It is known that cranberry inhibits the growth of Helicobacter pylori (HP). In human stomach, HP basically induces chronic inflammation by stimulating stomach cells to secrete interleukin (IL)-8 and other inflammatory cytokines, and causes stomach cancer, etc. The aim of this study was to investigate the inhibiting effects of cranberry on HP growth and IL-8 secretion from stomach cells induced by HP, using clinically separated HP strains. HP growth in liquid culture and on-plate culture was evaluated by titration after 2-day incubation and by agar dilution technique, respectively. For IL-8 experiments, MKN-45, a stomach cancer cell line, was incubated with HP for 24 h and IL-8 in the medium was assayed by ELISA. Cranberry suppressed growth of the bacteria only in six of the 27 strains. Meanwhile, it suppressed IL-8 secretion in all the strains. The results may suggest a possible role of cranberry in prevention of stomach cancer by reducing gastric inflammation.

American cranberry (Vaccinium macrocarpon) extract affects human prostate cancer cell growth via cell cycle arrest by modulating expression of cell cycle regulators

Posted: April 30, 2012
Authors: Deziel B, MacPhee J, Patel K, Catalli A, Kulka M, Neto C,
Journal: Food Funct DOI: 10.1039/c2fo10145a

Abstract: 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 mg 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 mg 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 p16INK4a and pRBp107 protein expression
levels also were evident, however, the changes noted in p16INK4a 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.

Cancer chemopreventive effect of fractions from cranberry products

Posted: April 30, 2012
Authors: Caillet S, Lorenzo G, Côté J, Doyon G, Sylvain JF, Lacroix M
Journal: Food Res Int 45;320–330

Abstract: "Cancer chemopreventive properties were evaluated in HPLC fractions of different polarity obtained from two
cranberry juices and three extracts isolated from frozen cranberries and pomace containing anthocyanins,
water-soluble and apolar phenolic compounds, respectively. Compounds with close polarities were collected in order to obtain between three and four fractions from each juice or extract. Cranberry fractions were screened for their ability to induce the phase II xenobiotic detoxification enzyme quinone reductase (QR).
The results showed that there was no cytotoxicity against the cells used in the test. All samples stimulated
the quinone reductase activity except the highest concentrations of the less polar fraction of anthocyaninrich extract from pomace, which inhibited the QR activity. The QR induction for all samples varied with the concentration and there was an optimal concentration for which the QR induction was maximal. The technological process to manufacture cranberry juice had little influence on the overall QR inducer potencies of
cranberry fractions, whereas the ability of phenols in fractions to stimulate the QR activity has been reduced
significantly (P&#8804;0.05) during the technological process. Among all samples, phenolic compounds of eight
fractions presented a maximum QR induction greater than 100 II(QR)/mg phenol. The phenolic compounds
of the most polar fraction (rich in phenolic acids) and those of the less polar fraction (rich in proanthocyanidins)
showed stronger induction than those observed with phenols from intermediate fractions."

Cranberry as Promising Natural Source of Potential Anticancer Agents: Current Evidence and Future Perspectives

Posted: April 30, 2012
Authors: Katsargyris A, Tampaki EC, Giaginis C, Theocharis S
Journal: Anticancer Agents Med Chem [Epub ahead of print]

Abstract: Accumulating evidence suggest that dietary modification can lower the risk for several cancer types' development. Cranberry in particular, has been shown to have anti-oxidative, -inflammatory and -proliferative properties in vitro. To present the latest knowledge regarding the role of cranberry extracts against human cancer several types. A review of the literature documenting both in vitro and in vivo anti-cancer effects of whole cranberry and/or its extracts is conducted; Current data provide evidence for several anti-cancer properties of either whole cranberry and/or its extracts. The discovery of the specific cranberry components and the appropriate concentrations that exert such beneficial effects along with verification of the preliminary in vitro results in in vivo settings could potentially lead to the invention of novel safer and efficient anti-cancer therapeutic agents.

Cranberry Juice Extract, A Mild Prooxidant with Cytotoxic Properties Independent of Reactive Oxygen Species

Posted: April 30, 2012
Authors: Babich H, Ickow IM, Weisburg JH, Zuckerbraun HL, Schuck AG
Journal: Phytother Res DOI: 10.1002/ptr.3735

Abstract: A cranberry juice extract (CJE), rich in proanthocyanidins, had weak prooxidant properties, generating low
levels of hydrogen peroxide (H2O2) and superoxide. Generation of H2O2 was pH dependent, increasing at
alkaline pH, and was lowered in the presence of catalase and, to a lesser extent, of superoxide dismutase
(SOD). Growth inhibition and cytotoxicity were noted towards human oral carcinoma HSC-2 cells, with midpoint
cytotoxicity at 200mg/mL CJE, but not towards human gingival HF-1 fibroblasts. Being a mild prooxidant,
CJE toxicity was unaffected by exogenous catalase and pyruvate, scavengers of H2O2, but triggered intracellular
synthesis of reduced glutathione, as confirmed by cell staining with Cell Tracker™ Green. The presence of
exogenous SOD potentiated the toxicity of CJE, possibly by stabilizing the CJE phenols and hindering their
degradative autooxidation. Conversely, ‘spent’ CJE, i.e. CJE added to cell culture medium and incubated for
24 h at 37 C prior to use, was much less toxic to HSC-2 cells than was freshly prepared CJE. These differences
in toxicity between SOD-stabilized CJE, freshly prepared CJE, and ‘spent’ CJE were confirmed in HSC-2 cells
stained with aceto-orcein, which also indicated that the mode of cell death was by the induction of apoptosis.

MicroRNA alterations in Barrett's esophagus, esophageal adenocarcinoma, and esophageal adenocarcinoma cell lines following cranberry extract treatment: Insights for chemoprevention

Posted: January 26, 2012
Authors: Kresty LA, Clarke J, Ezell K, Exum A, Howell AB, Guettouche T
Journal: J Carcinog 10:34. Epub 2011 Dec 22

Abstract: BACKGROUND: Aberrant expression of small noncoding endogenous RNA molecules known as microRNAs (miRNAs) is documented to occur in multiple cancer types including
esophageal adencarcinoma (EAC) and its only known precursor, Barrett's esophagus (BE). Recent studies have linked dysregulation of specific miRNAs to histological
grade, neoplastic progression and metastatic potential.
MATERIALS AND METHODS: Herein, we present a summary of previously reported dysregulated miRNAs in BE and EAC tissues as well as EAC cell lines and evaluate a cranberry proanthocyanidin rich extract's (C-PAC) ability to modulate miRNA expression patterns of three human EAC cell lines (JHEso-Ad-1, OE33 and OE19).
RESULTS: A review of 13 published studies revealed dysregulation of 87 miRNAs in BE and EAC tissues, whereas 52 miRNAs have been reported to be altered in BE or
EAC cell lines, with 48% overlap with miRNA changes reported in tissues. We report for the first time C-PAC-induced modulation of five miRNAs in three EAC
cell lines resulting in 26 validated gene targets and identification of key signaling pathways including p53, angiogenesis, T-cell activation and apoptosis.
Additionally, mutiple cancer related networks were ideintified as modulated by C-PAC utilizing Kyoto Encyclopedia of Genes and Genomes (KEGG), Protein Analysis Through Evolutionary Relationships (PANTHER), and MetaCore analysis tools.
CONCLUSIONS: Study results support the cancer inhibitory potential of C-PAC is in part attributable to C-PAC's ability to modify miRNA profiles within EAC cells. A number of C-PAC-modulated miRNAs have been been identified as dysregulated in BE and EAC. Further insights into miRNA dysregulation and modulation by select cancer preventive agents will support improved targeted interventions in
high-risk cohorts.

North American cranberry (Vaccinium macrocarpon) stimulates apoptotic pathways in DU145 human prostate cancer cells in vitro

Posted: January 26, 2012
Authors: MacLean MA, Scott BE, Deziel BA, Nunnelley MC, Liberty AM, Gottschall-Pass KT, Neto CC, Hurta RA
Journal: Nutr Cancer. 63(1):109-20

Abstract: Diets rich in fruits and vegetables have been shown to improve patient prognosis in a variety of cancers, a benefit partly derived from phytochemicals, many of which target cell death pathways in tumor cells. Cranberries (Vaccinium macrocarpon) are a phytochemical-rich fruit containing a variety of polyphenolic compounds. As flavonoids have been shown to induce apoptosis in human tumor cells, this study investigated the hypothesis that cranberry-mediated cytotoxicity in DU145 human prostate adenocarcinoma cells involves apoptosis. The results showed that induction of apoptosis in these cells occurred in response to treatment with whole cranberry extract and occurred through caspase-8 mediated cleavage of Bid protein to truncated Bid resulting in cytochrome-C release from the mitochondria. Subsequent activation of caspase-9 ultimately resulted in cell death as characterized by DNA fragmentation. Increased Par-4 protein expression was observed, and this is suggested to be at least partly responsible for caspase-8 activation. Proanthocyanidin-enriched and flavonol-enriched fractions of cranberry also increased caspase-8 and caspase-9 activity, suggesting that these compounds play a possible role in apoptosis induction. These findings indicate that cranberry phytochemicals can induce apoptosis in prostate cancer cells in vitro, and these findings further establish the potential value of cranberry phytochemicals as possible agents against prostate cancer.

Ursolic acid and its esters: occurrence in cranberries and other Vaccinium fruit and effects on matrix metalloproteinase activity in DU145 prostate tumor cells.

Posted: January 26, 2012
Authors: Kondo M, MacKinnon SL, Craft CC, Matchett MD, Hurta RAR, Neto CC
Journal: J Sci Food Agric 91: 5, 789-796

Abstract: Ursolic acid and its cis- and trans-3-O-p-hydroxycinnamoyl esters have been identified as constituents of American cranberries (Vaccinium macrocarpon), which inhibit tumor cell proliferation. Since the compounds may contribute to berry anticancer properties, their content in cranberries, selected cranberry products, and three other Vaccinium species (V. oxycoccus, V. vitis-idaea and V. angustifolium) was determined by liquid chromatography-mass spectroscopy. The ability of these compounds to inhibit growth in a panel of tumor cell lines and inhibit matrix metalloproteinase (MMP) activity associated with tumor invasion and metastasis was determined in DU145 prostate tumor cells. RESULTS: The highest content of ursolic acid and esters was found in V. macrocarpon berries (0.460-1.090 g ursolic acid and 0.040-0.160 g each ester kg-1 fresh weight). V. vitis-idaea and V. angustifolium contained ursolic acid (0.230-0.260 g kg-1), but the esters were not detected. V. oxycoccus was lowest (0.129 g ursolic acid and esters per kg). Ursolic acid content was highest in cranberry products prepared from whole fruit. Ursolic acid and its esters inhibited tumor cell growth at micromolar concentrations, and inhibited MMP-2 and MMP-9 activity at concentrations below those previously reported for cranberry polyphenolics. CONCLUSION: Cranberries (V. macrocarpon) were the best source of ursolic acid and its esters among the fruit and products tested. These compounds may limit prostate carcinogenesis through matrix metalloproteinase inhibition.

Effect of juice processing on the cancer chemopreventive effect of cranberry.

Posted: January 22, 2012
Authors: Caillet, S. Cote, J. Doyon, G. Sylvain, J. F. Lacroix, M
Journal: Food Res Int 44: 4, 902-910

Abstract: Cancer chemopreventive properties were evaluated in cranberries and cranberry products (mash, depectinized mash, pomace, raw juice, clarified juice and juice concentrate). Three extracts isolated from frozen cranberries and cranberry solids (mash, depectinized mash and pomace) containing anthocyanins, water-soluble and apolar phenolic compounds were tested. Cranberry juices and extracts were screened for their ability to induce the phase II xenobiotic detoxification enzyme quinone reductase (QR). The results showed that there was no cytotoxicity against the cells used in the test. All samples stimulated quinone reductase activity except the highest concentrations of the anthocyanin-rich extract of pomace, which inhibited QR activity. Also, the results showed that the QR induction for all samples varied with concentration and that there was an optimal concentration for which the QR induction was maximal. Although the three cranberry extracts were good QR inducers, our results indicated that the phenols present in aqueous extract showed QR inductions which were more important than those obtained with phenols present in solvent extracts. Also, the ability of phenols to stimulate the QR activity has been reduced continuously and significantly (P<=0.05) during the technological process. Especially, it appears that conditions of the evaporation to obtain a juice concentrate exerted a significant effect (P<=0.05) on inducer potencies of bioactive molecules.

Cranberries: ripe for more cancer research?

Posted: January 17, 2012
Authors: Neto CC
Journal: J Sci Food Agric 91: 13, 2303-2307

Abstract: Berries have been recognized as a functional food with potential to protect against a variety of health conditions, including some cancers. Cranberry (Vaccinium macrocarpon) production and consumption have grown in recent years, warranting further evaluation of potential health benefits. Extracts and isolated constituents from cranberry fruit inhibit growth and proliferation of tumor cells in vitro, and recent data from animal studies lend further support to cranberry's reputation as a cancer fighter. Several likely mechanisms of action for cranberry against prostate and other cancers have been identified, including induction of apoptosis and inhibition of events linked to cellular invasion and migration. This article attempts to put into perspective what is known about cranberry's potential chemopreventive properties, what is yet to be determined, and some factors to consider as research moves forward.

Cranberry proanthocyanidins mediate growth arrest of lung cancer cells through modulation of gene expression and rapid induction of apoptosis.

Posted: January 17, 2012
Authors: Kresty LA, Howell AB, Baird M
Journal: Molecules 16(3):2375-90

Abstract: Cranberries are rich in bioactive constituents purported to enhance immune function, improve urinary tract health, reduce cardiovascular disease and more recently, inhibit cancer in preclinical models. However, identification of the cranberry constituents with the strongest cancer inhibitory potential and the mechanism associated with cancer inhibition by cranberries remains to be elucidated. This study investigated the ability of a proanthocyanidin rich cranberry fraction (PAC) to alter gene expression, induce apoptosis and impact the cell cycle machinery of human NCI-H460 lung cancer cells. Lung cancer is the leading cause of cancer-related deaths in the United States and five year survival rates remain poor at 16%. Thus, assessing potential inhibitors of lung cancer-linked signaling pathways is an active area of investigation.

Effect of different cranberry extracts and juices during cranberry juice processing

Posted: January 17, 2012
Authors: Vu KD, Carlettini H, Bouvet J, Côté J, Doyon G, Sylvain J-F, Lacroix M
Journal: Food Chemistry 132 (2):959-967

Abstract: 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.

Anti-angiogenic activity of cranberry proanthocyanidins and cytotoxic properties in ovarian cancer cells

Posted: January 14, 2012
Authors: Kim KK, Singh AP, Singh RK, Demartino A, Brard L, Vorsa N, Lange TS, Moore RG
Journal: Int J Oncol 40(1):227-35.

Abstract: 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.

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 (&#8710;&#936;m) 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 &#956;gml&#8722;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 &#956;g/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 I&#954;B&#945; 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 I&#954;B&#945; was determined. The results indicated that cranberry extract and quercetin decreased COX-2 expression and suppressed degradation of I&#954;B&#945; in unstimulated cells. In PMA-stimulated cells, cranberry extract was also able to decrease COX-2 expression and suppress degradation of I&#954;B&#945;.
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&#8201;µg/ml by 30% after 6&#8201;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-&#954;B 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-&#954;B 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 < 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.

In vivo inhibition of growth of human tumor lines by flavonoid fractions from cranberry extract.

Posted: November 10, 2010
Authors: Ferguson PJ, Kurowska EM, Freeman DJ, Chambers AF and Koropatnick J
Journal: Nutr Cancer 56(1):86-94

Abstract: 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.

Selected fruits reduce azoxymethane (AOM)-induced aberrant crypt foci (ACF) in Fisher 344 male rats.

Posted: November 10, 2010
Authors: Boateng J, Verghese M, Shackelford L, Walker LT, Khatiwada J, Ogutu S, Williams DS, Jones J, Guyton M, Asiamah D, Henderson F, Grant L, DeBruce M, Johnson A, Washington S, Chawan CB.
Journal: Food Chem Toxicol 45(5):725-32

Abstract: 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.

Anticancer activities of cranberry phytochemicals: an update

Posted: November 9, 2010
Authors: Neto CC, Amoroso JW and Liberty AM
Journal: Mol Nutr Food Res 52(Suppl 1):S18-27

Abstract: 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.

Cranberry and its phytochemicals: a review of in vitro anticancer studies

Posted: November 9, 2010
Authors: Neto CC
Journal: J Nutr 137(1 Suppl):186S-193S

Abstract: 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.

Cranberry juice constituents impair lymphoma growth and augment the generation of antilymphoma antibodies in syngeneic mice

Posted: November 9, 2010
Authors: Hochman N, Houri-Haddad Y, Koblinski J, Wahl L, Roniger M, Bar-Sinai A, Weiss EI, Hochman J
Journal: Nutr Cancer 60(4):511-7

Abstract: 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.

Cranberry proanthocyanidins induce apoptosis and inhibit acid-induced proliferation of human esophageal adenocarcinoma cells.

Posted: November 9, 2010
Authors: Kresty LA, Howell AB, Baird M
Journal: J Agric Food Chem 56(3):676-80

Abstract: 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.

Blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts inhibit growth and stimulate apoptosis of human cancer cells in vitro

Posted: November 8, 2010
Authors: Seeram NP, Adams LS, Zhang Y, Lee R, Sand D, Scheuller HS, Heber D
Journal: J Agric Food Chem 54(25):9329-39

Abstract: Berry fruits are widely consumed in our diet and have attracted much attention due to their potential human health benefits. Berries contain a diverse range of phytochemicals with biological properties such as antioxidant, anticancer, anti-neurodegerative, and anti-inflammatory activities. In the current study, extracts of six popularly consumed berries--blackberry, black raspberry, blueberry, cranberry, red raspberry and strawberry--were evaluated for their phenolic constituents using high performance liquid chromatography with ultraviolet (HPLC-UV) and electrospray ionization mass spectrometry (LC-ESI-MS) detection. The major classes of berry phenolics were anthocyanins, flavonols, flavanols, ellagitannins, gallotannins, proanthocyanidins, and phenolic acids. The berry extracts were evaluated for their ability to inhibit the growth of human oral (KB, CAL-27), breast (MCF-7), colon (HT-29, HCT116), and prostate (LNCaP) tumor cell lines at concentrations ranging from 25 to 200 micro g/mL. With increasing concentration of berry extract, increasing inhibition of cell proliferation in all of the cell lines were observed, with different degrees of potency between cell lines. The berry extracts were also evaluated for their ability to stimulate apoptosis of the COX-2 expressing colon cancer cell line, HT-29. Black raspberry and strawberry extracts showed the most significant pro-apoptotic effects against this cell line. The data provided by the current study and from other laboratories warrants further investigation into the chemopreventive and chemotherapeutic effects of berries using in vivo models.

Effect of cranberry juice concentrate on chemically-induced urinary bladder cancers.

Posted: November 8, 2010
Authors: Prasain JK, Jones K, Moore R, Barnes S, Leahy M, Roderick R, Juliana MM, Grubbs CJ
Journal: Oncol Rep 19(6):1565-70

Abstract: The chemopreventive efficacy of cranberry juice concentrate in an experimental model of urinary bladder cancer was evaluated using female Fischer-344 rats. The animals received N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) for a period of eight weeks. Cranberry juice concentrate was administered at doses of 1.0 or 0.5 ml/rat/day beginning one week after the final OH-BBN treatment and continuing until the end of the study. The urinary bladders of all the rats were weighed and examined grossly for lesions, and all masses were submitted for pathological evaluation. A dose-dependent preventive effect of cranberry treatment was observed, with a reduced number of urinary bladder cancers (38%) in the 1.0 ml/rat/day group versus the control group. The cranberry extract neither affected body weight gain nor caused other signs of toxicity. For the metabolic studies, serum and urine were collected at 4 and 12 h after the administration of the cranberry juice concentrate and were analyzed by LC-MS/MS. Quercetin and its methylated derivative were detected in the urine samples. However, no quercetin was detected in the serum samples, indicating its poor bioavailability. These data suggest that components of cranberries may be effective in preventing urinary bladder carcinogenesis.

Total cranberry extract versus its phytochemical constituents: antiproliferative and synergistic effects against human tumor cell lines

Posted: November 6, 2010
Authors: Seeram NP, Adams LS, Hardy ML, Heber D
Journal: J Agric Food Chem 52(9):2512-7

Abstract: Cranberries (Vaccinium macrocarpon Ait.) are an excellent dietary source of phytochemicals that include flavonol glycosides, anthocyanins, proanthocyanidins (condensed tannins), and organic and phenolic acids. Using C-18 and Sephadex Lipophilic LH-20 column chromatography, HPLC, and tandem LC-ES/MS, the total cranberry extract (TCE) has been analyzed, quantified, and separated into fractions enriched in sugars, organic acids, total polyphenols, proanthocyanidins, and anthocyanins (39.4, 30.0, 10.6, 5.5, and 1.2% composition, respectively). Using a luminescent ATP cell viability assay, the antiproliferative effects of TCE (200 microg/mL) versus all fractions were evaluated against human oral (KB, CAL27), colon (HT-29, HCT116, SW480, SW620), and prostate (RWPE-1, RWPE-2, 22Rv1) cancer cell lines. The total polyphenol fraction was the most active fraction against all cell lines with 96.1 and 95% inhibition of KB and CAL27 oral cancer cells, respectively. For the colon cancer cells, the antiproliferative activity of this fraction was greater against HCT116 (92.1%) than against HT-29 (61.1%), SW480 (60%), and SW620 (63%). TCE and all fractions showed >/=50% antiproliferative activity against prostate cancer cells with total polyphenols being the most active fraction (RWPE-1, 95%; RWPE-2, 95%; 22Rv1, 99.6%). Cranberry sugars (78.8 microg/mL) did not inhibit the proliferation of any cancer cell lines. The enhanced antiproliferative activity of total polyphenols compared to TCE and its individual phytochemicals suggests synergistic or additive antiproliferative interactions of the anthocyanins, proanthocyanidins, and flavonol glycosides within the cranberry extract.

Antioxidant activities and antitumor screening of extracts from cranberry fruit (Vaccinium macrocarpon)

Posted: November 5, 2010
Authors: Yan X, Murphy BT, Hammond GB, Vinson JA, Neto CC
Journal: J Agric Food Chem 50(21):5844-9

Abstract: Polyphenolic compounds in cranberries have been investigated to determine their role in protection against cardiovascular disease and some cancers. Extracts of whole fruit were assayed for radical-scavenging activity and tumor growth inhibition using seven tumor cell lines. Selective inhibition of K562 and HT-29 cells was observed from a methanolic extract in the range of 16-125 microg/mL. Radical-scavenging activity was greatest in an extract composed primarily of flavonol glycosides. Seven flavonol glycosides were isolated and purified from whole fruit for further evaluation; the anthocyanin cyanidin 3-galactoside was also purified for comparison with the flavonoids. Three flavonol monoglycosides were newly identified by (13)C NMR as myricetin 3-alpha-arabinofuranoside, quercetin 3-xyloside, and 3-methoxyquercetin 3-beta-galactoside (isorhamnetin); the other four isolated were the previously identified myricetin 3-beta-galactoside, quercetin 3-beta-galactoside, quercetin 3-alpha-arabinofuranoside, and quercetin 3-alpha-rhamnopyranoside. These compounds were evaluated for 1,1-diphenyl-2-picrylhydrazyl radical-scavenging activity and ability to inhibit low-density lipoprotein oxidation in vitro. Most of the flavonol glycosides showed antioxidant activity comparable or superior to that of vitamin E; cyanidin 3-galactoside showed activity superior to that of the flavonoids as well as vitamin E or Trolox in both antioxidant assays.

Cranberry (Vaccinium macrocarpon) protects against doxorubicin-induced cardiotoxicity in rats

Posted: November 4, 2010
Authors: Elberry AA, Abdel-Naim AB, Abdel-Sattar EA, Nagy AA, Mosli HA, Mohamadin AM, Ashour OM.
Journal: Food Chem Toxicol 48(5):1178-84

Abstract: Doxorubicin (DOX) is a widely used cancer chemotherapeutic agent. However, it generates free oxygen radicals that result in serious dose-limiting cardiotoxicity. Supplementations with berries were proven effective in reducing oxidative stress associated with several ailments. The aim of the current study was to investigate the potential protective effect of cranberry extract (CRAN) against DOX-induced cardiotoxicity in rats. CRAN was given orally to rats (100mg/kg/day for 10 consecutive days) and DOX (15mg/kg; i.p.) was administered on the seventh day. CRAN protected against DOX-induced increased mortality and ECG changes. It significantly inhibited DOX-provoked glutathione (GSH) depletion and accumulation of oxidized glutathione (GSSG), malondialdehyde (MDA), and protein carbonyls in cardiac tissues. The reductions of cardiac activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were significantly mitigated. Elevation of cardiac myeloperoxidase (MPO) activity in response to DOX treatment was significantly hampered. Pretreatment of CRAN significantly guarded against DOX-induced rise of serum lactate dehydrogenase (LDH), creatine phosphokinase (CK), creatine kinase-MB (CK-MB) as well as troponin I level. CRAN alleviated histopathological changes in rats' hearts treated with DOX. In conclusion, CRAN protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to CRAN's antioxidant activity.

Cranberry phytochemical extract inhibits SGC-7901 cell growth and human tumor xenografts in Balb/c nu/nu mice

Posted: November 4, 2010
Authors: Liu M, Lin LQ, Song BB, Wang LF, Zhang CP, Zhao JL, Liu JR
Journal: J Agric Food Chem 57(2):762-8

Abstract: Cranberry extract possesses potent antioxidant capacity and antiproliferative activity against cancer in vitro and in vivo. The objectives of this study were to determine whether the cranberry extract inhibited proliferation of human gastric cancer SGC-7901 cells and human gastric tumor xenografts in the Balb/c nu/nu mouse. Cranberry extract at doses of 0, 5, 10, 20, and 40 mg/mL significantly inhibited proliferation of SGC-7901 cells, and this suppression was partly attributed to decreased PCNA expression and apoptosis induction. In a human tumor xenograft model, the time of human gastric tumor xenografts in the mouse was delayed in a dose-dependent manner. A dose-response inhibition was also observed in the averages of size, weight, and volume of tumor xenografts in the mouse between the control and cranberry-treated groups. These results demonstrate fresh cranberries to be a chemopreventive reagent.

Cranberry phytochemical extracts induce cell cycle arrest and apoptosis in human MCF-7 breast cancer cells.

Posted: November 4, 2010
Authors: Sun J, Hai Liu R.
Journal: Cancer Lett 241(1):124-34

Abstract: Breast cancer is the most commonly diagnosed cancer in women in the US and is one of the leading causes of death due to cancer. Epidemiological studies have consistently suggested the inverse association between cancer risk and intake of fruits and vegetables. These health benefits have been linked to the additive and synergistic combination of phytochemicals in fruits and vegetables. Cranberries have been shown to possess anti-carcinogenic activities such as inhibition of growth of several cancer cell lines, and inhibition of ornithine decarboxylase (ODC) activity in vitro. However, the molecular mechanisms of the anti-cancer properties of cranberry phytochemical extracts have not been completely understood. Our data showed that cranberry phytochemical extracts significantly inhibited human breast cancer MCF-7 cell proliferation at doses of 5 to 30mg/mL (P<0.05). Apoptotic induction in MCF-7 cells was observed in a dose-dependent manner after exposure to cranberry phytochemical extracts for 4h. Cranberry phytochemical extracts at a dose of 50mg/mL resulted in a 25% higher ratio of apoptotic cells to total cells as compared to the control groups (P<0.05). Cranberry phytochemical extracts at doses from 10 to 50mg/mL significantly arrested MCF-7 cells at G0/G1 phase (P<0.05). A constant increasing pattern of the G1/S index was observed in the cranberry extract treatment group while the G1/S ratio of the control group decreased concomitantly between 10 and 24h treatment. After 24-h exposure to cranberry extracts, the G1/S index of MCF-7 cells was approximately 6 times higher than that of the control group (P<0.05). These results suggest that cranberry phytochemical extracts possess the ability to suppress the proliferation of human breast cancer MCF-7 cells and this suppression is at least partly attributed to both the initiation of apoptosis and the G1 phase arrest.

Cranberry proanthocyanidins are cytotoxic to human cancer cells and sensitize platinum-resistant ovarian cancer cells to paraplatin

Posted: November 2, 2010
Authors: Singh AP, Singh RK, Kim KK, Satyan KS, Nussbaum R, Torres M, Brard L and Vorsa N
Journal: Phytother Res 23(8):1066-74

Abstract: Polyphenolic extracts of the principal flavonoid classes present in cranberry were screened in vitro for cytotoxicity against solid tumor cells lines, identifying two fractions composed principally of proanthocyanidins (PACs) with potential anticancer activity. Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF-MS) analysis of the proanthocyanidins (PACs) fractions indicated the presence of A-type PACs with 1-4 linkages containing between 2-8 epicatechin units with a maximum of 1 epigallocatechin unit. PACs exhibited in vitro cytotoxicity against platinum-resistant human ovarian, neuroblastoma and prostate cancer cell lines (IC50 = 79-479 microg/mL) but were non-cytotoxic to lung fibroblast cells (IC50 > 1000 microg/ml). SKOV-3 ovarian cancer cells treated with PACs exhibited classic apoptotic changes. PACs acted synergistically with paraplatin in SKOV-3 cells. Pretreatment of SKOV-3 cells with PACs (106 microg/ml) resulted in a significant reduction of the paraplatin IC50 value. Similarly, in a BrdU incorporation assay, co-treatment of SKOV-3 cells with PACs and paraplatin revealed reduced cell proliferation at lower concentrations than with either individually. In SKOV-3 cell cultures co-treated with PAC-1 and paraplatin, an HPLC analysis indicated differential quantitative presence of various PAC oligomers such as DP-8, -9, -11 and -14 indicating either selective binding or uptake. Cranberry proanthocyanidins exhibit cell-line specific cytotoxicity, induce apoptotic markers and augment cytotoxicity of paraplatin in platinum-resistant SKOV-3 ovarian cancer cells.

A Flavonoid Fraction from Cranberry Extract Inhibits Proliferation of Human Tumor Cell Lines

Posted: October 13, 2010
Authors: Ferguson PJ,Kurowska E, Freeman DJ, Chambers AF,
Journal: J Nutr 134:1529-1535

Abstract: In light of the continuing need for effective anticancer agents, and the association of fruit and vegetable consumption with reduced cancer risk, edible plants are increasingly being considered as sources of
anticancer drugs. Cranberry presscake (the material remaining after squeezing juice from the berries), when fed to mice bearing human breast tumor MDA-MB-435 cells, was shown previously to decrease the growth and
metastasis of tumors. Therefore, further studies were undertaken to isolate the components of cranberry that
contributed to this anticancer activity, and determine the mechanisms by which they inhibited proliferation. Using
standard chromatographic techniques, a warm-water extract of cranberry presscake was fractionated, and an
acidified methanol eluate (Fraction 6, or Fr6) containing flavonoids demonstrated antiproliferative activity. The
extract inhibited proliferation of 8 human tumor cell lines of multiple origins. The androgen-dependent prostate cell
line LNCaP was the most sensitive of those tested (10 mg/L Fr6 inhibited its growth by 50%), and the estrogen independent breast line MDA-MB-435 and the androgen-independent prostate line DU145 were the least sensitive
(250 mg/L Fr6 inhibited their growth by 50%). Other human tumor lines originating from breast (MCF-7), skin
(SK-MEL-5), colon (HT-29), lung (DMS114), and brain (U87) had intermediate sensitivity to Fr6. Using flow
cytometric analyses of DNA distribution (cell cycle) and annexin V-positivity (apoptosis), Fr6 was shown in
MDA-MB-435 cells to block cell cycle progression (P 0.05) and induce cells to undergo apoptosis (P 0.05) in
a dose-dependent manner. Fr6 is potentially a source of a novel anticancer agent.