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Oncology/Anti-Cancer

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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≤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.

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