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Oncology/Anti-Cancer: In-Vitro

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

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

Posted
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
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
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.