Treatment of Mcf-7 Breast Cancer Cells with a Red Grape Wine Polyphenol Fraction Results in Disruption of Calcium Homeostasis and Cell Cycle Arrest Causing Selective Cytotoxicity

Hakimuddin, Fatima; Paliyath, Gopinadhan; Meckling, Kelly A.

doi:10.1021/jf060834m

Cited by 42 publications

(33 citation statements)

References 39 publications

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“…Although red wine has been reported to exert anticarcinogenic effects, including growth inhibition of some cancer cells (28,29), the underlying mechanisms and molecular targets remain unclear. In the present study, we found that RWE inhibited TPA-induced neoplastic transformation of JB6 P+ cells.…”

Section: Discussionmentioning

confidence: 99%

Raf and MEK Protein Kinases Are Direct Molecular Targets for the Chemopreventive Effect of Quercetin, a Major Flavonol in Red Wine

et al. 2008

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Considerable attention has focused on the health-promoting effects of red wine and its nonflavonoid polyphenol compound resveratrol. However, the underlying molecular mechanisms and molecular target(s) of red wine or other potentially active ingredients in red wine remain unknown. Here, we report that red wine extract (RWE) or the red wine flavonoid quercetin inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced transformation of JB6 promotion-sensitive mouse skin epidermal (JB6 P+) cells. The activation of activator protein-1 and nuclear factor-KB induced by TPA was dose dependently inhibited by RWE or quercetin treatment. Western blot and kinase assay data revealed that RWE or quercetin inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) 1 and Raf1 kinase activities and subsequently attenuated TPAinduced phosphorylation of ERK/p90 ribosomal S6 kinase. Although either RWE or quercetin suppressed Raf1 kinase activity, they were more effective in inhibiting MEK1 activity. Importantly, quercetin exerted stronger inhibitory effects than PD098059, a well-known pharmacologic inhibitor of MEK. Resveratrol did not affect either MEK1 or Raf1 kinase activity. Pull-down assays revealed that RWE or quercetin (but not resveratrol) bound with either MEK1 or Raf1. RWE or quercetin also dose dependently suppressed JB6 P+ cell transformation induced by epidermal growth factor or H-Ras, both of which are involved in the activation of MEK/ ERK signaling. Docking data suggested that quercetin, but not resveratrol, formed a hydrogen bond with the backbone amide group of Ser 212 , which is the key interaction for stabilizing the inactive conformation of the activation loop of MEK1. [Cancer Res 2008;68(3):946-55]

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Section: Discussionmentioning

confidence: 99%

Raf and MEK Protein Kinases Are Direct Molecular Targets for the Chemopreventive Effect of Quercetin, a Major Flavonol in Red Wine

et al. 2008

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“…Because of its central role in calcium homeostasis, it is conceivable that RYR3 plays a role in breast calcification. Calcium channels are important for calcium homeostasis, which is associated with physiological and pathophysiological processes of the mammary gland, and may represent potential drug targets for the treatment of breast cancer (10)(11)(12).…”

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confidence: 99%

Functional SNP in the microRNA-367 binding site in the 3′UTR of the calcium channel ryanodine receptor gene 3 ( RYR3 ) affects breast cancer risk and calcification

Zhang

Liu

Song

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

145

106

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We have evaluated and provided evidence that the ryanodine receptor 3 gene (RYR3), which encodes a large protein that forms a calcium channel, is important for the growth, morphology, and migration of breast cancer cells. A putative binding site for microRNA-367 (miR-367) exists in the 3′UTR of RYR3, and a genetic variant, rs1044129 A→G, is present in this binding region. We confirmed that miR-367 regulates the expression of a reporter gene driven by the RYR3 3′UTR and that the regulation was affected by the RYR3 genotype. A thermodynamic model based on base pairing and the secondary structure of the RYR3 mRNA and miR-367 miRNA showed that miR-367 had a higher binding affinity for the A genotype than for the G genotype. The rs1044129 SNP was genotyped in 1,532 breast cancer cases and 1,600 healthy Chinese women. The results showed that compared with the AA genotype, G was a risk genotype for breast cancer development and was also associated with breast cancer calcification and poor survival. Thus, rs1044129 is a unique SNP that resides in a miRNA-gene regulatory loop that affects breast cancer risk, calcification, and survival.

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“…As noted in the introduction, there have been many studies suggesting effectiveness of berry extracts or polyphenol components against cancer cells and these have often been followed by studies unravelling the possible mechanisms for selective cytotoxicity such as influencing signal transduction pathways (41) and disruption of calcium homeostasis (22) or cell cycle control (41). However, fewer studies have incorporated controls using 'normal' cells and often these cells are non-identical or non-equivalent to the physiological origin of the cancer cells.…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

“…In addition, ellagic acid was more cytotoxic against normal than the pre-malignant and malignant oral cell lines (20). Red wine polyphenols were equally cytotoxic against normal human mammary epithelial cells and the tumourigenic breast epithelial cell line MCF-7 (49) although sub-fractions of unknown composition showed some selectivity towards the tumourigenic cell line (22,49). On the other hand, polyphenol-rich cocoa extracts were differentially cytotoxic against prostate cancer cell lines DU145 and 22Rv1 compared to a normal prostate epithelial cell line (21).…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

“…Cocoa extracts had a differential effect on prostate cancer cell lines DU145 and 22Rv1 compared to a normal prostate epithelial cell line (21). Red wine polyphenols were reported to have selective cytotoxicity against human breast cancer cells over normal cell lines (22). Studies on the responses of colon cancer and normal gastric mucosal cells to gallotannin and proanthocyanidin extracts (11,23) indicated that they have differential cytotoxic effects and proanthocyanidins enhanced the growth of the normal gastric mucosal cells (11).…”

Section: Introductionmentioning

confidence: 99%

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Strawberry polyphenols are equally cytotoxic to tumourigenic and normal human breast and prostate cell lines

Weaver

Briscoe²,

Hou³

et al. 2009

Int J Oncol

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Abstract. The cytotoxic effects of strawberry polyphenols were investigated on normal cells and tumour cells derived from the same patient. A human prostate epithelial cell line (P21) and two tumour cell lines (P21 tumour cell line 1 and 2) derived from the same patient, and a normal human breast epithelial cell line (B42) and a tumour line derived from it (B42 clone 16) were used. A polyphenol-rich extract derived from strawberry or anthocyanin or tannin-rich sub-fractions were applied to the cell lines in doses varying from 50 to 1.5 μg/ml. The strawberry extract was cytotoxic with doses of ~5 μg/ml causing a 50% reduction in cell survival in both the normal and the tumour lines. The extracts were also cytotoxic to peripheral blood human lymphocytes stimulated with phytohaemagglutinin but higher levels (>20 μg/ml for 50% reduction in cell survival) were required. After fractionation of the strawberry sample, the cytotoxicity was retained in the tannin-rich fraction and this fraction was considerably more toxic to all cells (normal or tumour cell lines or lymphocytes) than the anthocyanin-rich fraction. Established prostate (LNCaP and PC-3) and breast (MCF-7) tumour cell lines were more resistant to the strawberry extract with concentrations of 50 μg/ml required for 50% reduction in cell survival, which is similar to levels in previous studies on the antiproliferative effects of berry extracts. Although these concentrations are much greater than possible physiological levels, they are comparable to those reported in other studies. From these findings, we conclude that there is little evidence to assume that polyphenols from strawberry have a differential cytotoxic effect on tumour cells relative to comparable normal cells from the same tissue derived from the same patient.

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Treatment of Mcf-7 Breast Cancer Cells with a Red Grape Wine Polyphenol Fraction Results in Disruption of Calcium Homeostasis and Cell Cycle Arrest Causing Selective Cytotoxicity

Cited by 42 publications

References 39 publications

Raf and MEK Protein Kinases Are Direct Molecular Targets for the Chemopreventive Effect of Quercetin, a Major Flavonol in Red Wine

Raf and MEK Protein Kinases Are Direct Molecular Targets for the Chemopreventive Effect of Quercetin, a Major Flavonol in Red Wine

Functional SNP in the microRNA-367 binding site in the 3′UTR of the calcium channel ryanodine receptor gene 3 ( RYR3 ) affects breast cancer risk and calcification

Strawberry polyphenols are equally cytotoxic to tumourigenic and normal human breast and prostate cell lines

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