Breast Cancer Research and Treatment

, Volume 85, Issue 1, pp 65–79 | Cite as

Selective Cytotoxicity of a Red Grape Wine Flavonoid Fraction Against MCF-7 Cells

  • Fatima Hakimuddin
  • Gopinadhan Paliyath
  • Kelly Meckling


Red wine is a rich source of polyphenolic components such as anthocyanins and flavonoids. The inhibitory effects of red wine polyphenolics on human breast cancer cells have been demonstrated earlier, but their effects on normal cells have not been fully established. Red wine (Merlot) was fractionated by hydrophobic interaction chromatography and different flavonoid fractions with increasing hydrophobicity were obtained. These fractions were tested for their inhibitory effect on human breast cancer cells (MCF-7), normal human mammary epithelial cells (HMEC), and a non-tumorigenic MCF-10A cell line. By contrast to the authentic flavonoids such as quercetin, naringenin and catechin which inhibited the growth of HMEC much more than that of MCF-7 cancer cells, a red wine fraction, that was comprised mainly of the flavonoid aglycones, showed maximal inhibition of the growth of breast cancer cells, with relatively low cytotoxicity towards HMEC and MCF-10A cells. In the presence of this flavonoid fraction, the normal cells grew normally, whereas the breast cancer cells underwent a change in morphology into spherical forms. Cytotoxicity analyses suggested that these cells had become apoptotic. The efficiency of inhibition of cell proliferation by various flavonoid fractions appeared to be related to their inhibition of calcium and calmodulin-promoted phosphodiesterase activity, suggesting that flavonoids may interfere with calcium second messenger function. The results suggest that certain grape wine ingredients have anticancer properties and these ingredients may be helpful for developing designer functional foods with cancer-preventive properties.

breast cancer calmodulin flavonoids HMEC MCF-7 MCF-10A red wine 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    National Cancer Institute of Canada: Canadian Cancer Statistics 1995. Natl Cancer Institute, Toronto, Ontario, 402, 1995Google Scholar
  2. 2.
    Steinmetz KA, Potter JD: Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 2: 325–357, 1991Google Scholar
  3. 3.
    Block G, Patterson B, Subar A: Fruit, vegetables, and cancer prevention: a review of the epidemiologic evidence. Nutr Cancer 18: 1–29, 1992Google Scholar
  4. 4.
    Kondo K, Matsumoto A, Kurata H, Tananashi H, Koda H, Amachi T, Itakura H: Inhibition of oxidation of low-density lipoprotein with red wine. Lancet 344: 1152, 1994Google Scholar
  5. 5.
    Whitehead TP, Robinson D, Allaway S, Syms J, Hale A: Effect of red wine ingestion on the antioxidant capacity of serum. Clin Chem 41: 32–35, 1995Google Scholar
  6. 6.
    Lavy A, Fuhrman B, Markel A, Dankner G, Ben-Amotz A, Presser D, Aviram M: Effect of dietary supplementation of red or white wine on human blood chemistry, haematology, and coagulation: favourable effect of red wine on plasma high-density lipoprotein. Ann Nutr Metab 38: 287–294, 1994Google Scholar
  7. 7.
    Hertog MGL, Feskens EJM, Hollman PCH, Katan MB, Kromhout D: Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen elderly study. Lancet 342: 1007–1011, 1993Google Scholar
  8. 8.
    Damianaki A, Bakogcorgou E, Kampa M, Notas G, Hatzoglou A, Panagiotou S, Gemetzi C, Kouroumalis E, Martin PM, Castanas E: Potent inhibitory action of red wine polyphenols on human breast cancer cells. J Cell Biochem 78: 429–441, 2000Google Scholar
  9. 9.
    Clifford AJ, Ebeler SE, Ebeler JD, Bills ND, Hinrichs SH, Teissedre PL, Waterhouse AL: Delayed tumor onset in transgenic mice fed an amino-acid based diet supplemented with red wine solids. Am J Clin Nutr 64: 748–756, 1996Google Scholar
  10. 10.
    Zhang Y, Kreger BE, Dorgan JF, Splansky GL, Cupples LA, Ellison RC: Alcohol consumption and risk of breast cancer. The Framingham study revisited. Am J Epidemiol 149: 93–101, 1999Google Scholar
  11. 11.
    Smith-Warner SA, Spiegelman D, Yaun S-S, Brandt PA, Folsom AR, Goldbohm RA, Graham S, Holmberg L, Howe GR, Marshall JR, Miller AB, Potter JD, Speizer FE, Willett WC, Wolk A, Hunter DJ: Alcohol and breast cancer in women. JAMA 279: 535–540, 1998Google Scholar
  12. 12.
    Berridge MJ: Cellular control through interactions between cyclic nucleotides and calcium. Adv Cyclic Nucleotide Protein Phosphor Res 17: 329–335, 1984Google Scholar
  13. 13.
    Strobl JS, Peterson VA, Woodfork KA: A survey of human breast cancer sensitivity to growth inhibition by calmodulin antagonists in tissue culture. Biochem Pharmacol 47: 2157–2161, 1994Google Scholar
  14. 14.
    Rice-Evans CA, Packer L (eds): Flavonoids in Health and Disease. Marcel Dekker Inc, NewYork, 1998Google Scholar
  15. 15.
    Eberhardt MV, Lee CY, Liu RH: Antioxidant activity of fresh apples. Nature 405: 903–904, 2000Google Scholar
  16. 16.
    Paliyath G, Poovaiah BW: Calmodulin inhibitor in senescing apples and its physiological and pharmacological significance. Proc Natl Acad Sci USA 81: 2065–2069, 1984Google Scholar
  17. 17.
    Paliyath G, Poovaiah BW: Identification of naturally occurring calmodulin inhibitors and their effect on calcium-and calmodulin promoted protein phosphorylation. Plant Cell Physiol 26: 201–209, 1985Google Scholar
  18. 18.
    Pinhero RG, Paliyath G: Antioxidant and calmodulin inhibitory activities of phenolic components in fruit wines and its biotechnological implications. Food Biotechnol 15: 179–192, 2001Google Scholar
  19. 19.
    So F, Guthrie N, Chambers AF, Moussa M, Carroll KK: Inhibition of breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer 26: 167–181, 1996Google Scholar
  20. 20.
    Kuntz S, Wenzel U, Daniel H: Comparative analysis of the effects of flavonoids on proliferation, cytotoxicity, and apoptosis in human colon cancer cell lines. Eur J Nutr 38: 133–142, 1999Google Scholar
  21. 21.
    Velioglu YS, Mazza G, Gao L, Oomah BD: Antioxidant activity and total phenolics in selected fruits, vegetables, and grain products. J Agric Food Chem 46: 4113–4117, 1998Google Scholar
  22. 22.
    Wang J, Sporns P: Analysis of anthocyanins in red wine and fruit juice using MALDI-MS. J Agric Food Chem 47: 2009–2015, 1999Google Scholar
  23. 23.
    Atkinson TG, Meckling-Gill KA: Regulation of nucleoside drug toxicity by transport inhibitors and omega-3 polyunsaturated fatty acids in normal and transformed rat-2 fibroblasts. Cell Pharmacol 2: 259–264, 1995Google Scholar
  24. 24.
    Middleton Jr E, Kandaswami C: Potential health promoting properties of citrus flavonoids. Food Tech 48: 115–119, 1994Google Scholar
  25. 25.
    Frankel EN, Kanner J, German JB, Parks E, Kinsella JE: Inhibition of oxidation of low-density lipoprotein by phenolic substances in red wine. Lancet 341: 454–457, 1993Google Scholar
  26. 26.
    Renaud S, de Lorgeril M: Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339: 1523–1526, 1992Google Scholar
  27. 27.
    Furhman B, Lavy A, Aviram M: Consumption of red wine with meals reduces the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation. Am J Clin Nutr 61: 549–554, 1995Google Scholar
  28. 28.
    Pardee AB: A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA 71: 1286–1290, 1974Google Scholar
  29. 29.
    Kamei H, Hashimoto Y, Koide T, Kojima T, Hasegawa M: Anti-tumor effect of methanol extracts from red and white wines. Cancer Biotherapy Radiopharmaceuticals 13: 447–452, 1998Google Scholar
  30. 30.
    Veigl ML, Sedwick WD, Vanaman TC: Calcium and calmodulin in cell growth and transformation. Biochim Biophys Acta 738: 21–48, 1984Google Scholar
  31. 31.
    Hait WN, Lazo JS: Calmodulin: a potential target for cancer chemotherapeutic agents. J Clin Oncol 4: 994–1012, 1986Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Fatima Hakimuddin
    • 1
  • Gopinadhan Paliyath
    • 1
    • 2
  • Kelly Meckling
    • 3
  1. 1.Department of Food ScienceUniversity of GuelphGuelphCanada
  2. 2.Department of Plant AgricultureUniversity of GuelphGuelphCanada
  3. 3.Department of Human Biology and Nutritional SciencesUniversity of GuelphGuelphCanada

Personalised recommendations