Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

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


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.

This is a preview of subscription content, log in to check access.


  1. 1.

    National Cancer Institute of Canada: Canadian Cancer Statistics 1995. Natl Cancer Institute, Toronto, Ontario, 402, 1995

  2. 2.

    Steinmetz KA, Potter JD: Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 2: 325–357, 1991

  3. 3.

    Block G, Patterson B, Subar A: Fruit, vegetables, and cancer prevention: a review of the epidemiologic evidence. Nutr Cancer 18: 1–29, 1992

  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, 1994

  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, 1995

  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, 1994

  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, 1993

  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, 2000

  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, 1996

  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, 1999

  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, 1998

  12. 12.

    Berridge MJ: Cellular control through interactions between cyclic nucleotides and calcium. Adv Cyclic Nucleotide Protein Phosphor Res 17: 329–335, 1984

  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, 1994

  14. 14.

    Rice-Evans CA, Packer L (eds): Flavonoids in Health and Disease. Marcel Dekker Inc, NewYork, 1998

  15. 15.

    Eberhardt MV, Lee CY, Liu RH: Antioxidant activity of fresh apples. Nature 405: 903–904, 2000

  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, 1984

  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, 1985

  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, 2001

  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, 1996

  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, 1999

  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, 1998

  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, 1999

  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, 1995

  24. 24.

    Middleton Jr E, Kandaswami C: Potential health promoting properties of citrus flavonoids. Food Tech 48: 115–119, 1994

  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, 1993

  26. 26.

    Renaud S, de Lorgeril M: Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339: 1523–1526, 1992

  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, 1995

  28. 28.

    Pardee AB: A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA 71: 1286–1290, 1974

  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, 1998

  30. 30.

    Veigl ML, Sedwick WD, Vanaman TC: Calcium and calmodulin in cell growth and transformation. Biochim Biophys Acta 738: 21–48, 1984

  31. 31.

    Hait WN, Lazo JS: Calmodulin: a potential target for cancer chemotherapeutic agents. J Clin Oncol 4: 994–1012, 1986

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hakimuddin, F., Paliyath, G. & Meckling, K. Selective Cytotoxicity of a Red Grape Wine Flavonoid Fraction Against MCF-7 Cells. Breast Cancer Res Treat 85, 65–79 (2004).

Download citation

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