Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of mammary tumor growth and metastases to bone and liver by dietary grape polyphenols

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

The cancer preventive properties of grape products such as red wine have been attributed to polyphenols enriched in red wine. However, much of the studies on cancer preventive mechanisms of grape polyphenols have been conducted with individual compounds at concentrations too high to be achieved via dietary consumption. We recently reported that combined grape polyphenols at physiologically relevant concentrations are more effective than individual compounds at inhibition of ERα(−), ERβ(+) MDA-MB-231 breast cancer cell proliferation, cell cycle progression, and primary mammary tumor growth (Schlachterman et al., Transl Oncol 1:19–27, 2008). Herein, we show that combined grape polyphenols induce apoptosis and are more effective than individual resveratrol, quercetin, or catechin at inhibition of cell proliferation, cell cycle progression, and cell migration in the highly metastatic ER (−) MDA-MB-435 cell line. The combined effect of dietary grape polyphenols (5 mg/kg each resveratrol, quercetin, and catechin) was tested on progression of mammary tumors in nude mice created from green fluorescent protein-tagged MDA-MB-435 bone metastatic variant. Fluorescence image analysis of primary tumor growth demonstrated a statistically significant decrease in tumor area by dietary grape polyphenols. Molecular analysis of excised tumors demonstrated that reduced mammary tumor growth may be due to upregulation of FOXO1 (forkhead box O1) and NFKBIA (IκBα), thus activating apoptosis and potentially inhibiting NfκB (nuclear factor κB) activity. Image analysis of distant organs for metastases demonstrated that grape polyphenols reduced metastasis especially to liver and bone. Overall, these results indicate that combined dietary grape polyphenols are effective at inhibition of mammary tumor growth and site-specific metastasis.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Schlachterman A, Valle F, Wall KM, Azios NG, Castillo L, Morell L, Washington AV, Cubano LA, Dharmawardhane SF (2008) Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl Oncol 1:19–27

    PubMed  Google Scholar 

  2. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96. doi:10.3322/CA.2007.0010

    Article  PubMed  Google Scholar 

  3. Rastelli F, Crispino S (2008) Factors predictive of response to hormone therapy in breast cancer. Tumori 94:370–383

    PubMed  Google Scholar 

  4. Peregrin T (2005) Wine—a drink to your health? J Am Diet Assoc 105:1053–1054. doi:10.1016/j.jada.2005.05.016

    Article  PubMed  Google Scholar 

  5. de Lorimier AA (2000) Alcohol, wine, and health. Am J Surg 180:357–361. doi:10.1016/S0002-9610(00)00486-4

    Article  PubMed  Google Scholar 

  6. Aggarwal BB, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71:1397–1421. doi:10.1016/j.bcp.2006.02.009

    Article  PubMed  CAS  Google Scholar 

  7. Park EJ, Pezzuto JM (2002) Botanicals in cancer chemoprevention. Cancer Metastasis Rev 21:231–255. doi:10.1023/A:1021254725842

    Article  PubMed  CAS  Google Scholar 

  8. Damianaki A, Bakogeorgou E, Kampa M, Notas G, Hatzoglou A, Panagiotou S, Gemetzi C, Kouroumalis E, Martin PM, Castanas E (2000) Potent inhibitory action of red wine polyphenols on human breast cancer cells. J Cell Biochem 78:429–441. doi:10.1002/1097-4644(20000901)78:3<429::AID-JCB8>3.0.CO;2-M

    Article  PubMed  CAS  Google Scholar 

  9. Hakimuddin F, Paliyath G, Meckling K (2004) Selective cytotoxicity of a red grape wine flavonoid fraction against MCF-7 cells. Breast Cancer Res Treat 85:65–79. doi:10.1023/B:BREA.0000021048.52430.c0

    Article  PubMed  CAS  Google Scholar 

  10. Faustino RS, Sobrattee S, Edel AL, Pierce GN (2003) Comparative analysis of the phenolic content of selected Chilean, Canadian and American Merlot red wines. Mol Cell Biochem 249:11–19. doi:10.1023/A:1024745513314

    Article  PubMed  CAS  Google Scholar 

  11. Nigdikar SV, Williams NR, Griffin BA, Howard AN (1998) Consumption of red wine polyphenols reduces the susceptibility of low-density lipoproteins to oxidation in vivo. Am J Clin Nutr 68:258–265

    PubMed  CAS  Google Scholar 

  12. Delmas D, Lancon A, Colin D, Jannin B, Latruffe N (2006) Resveratrol as a chemopreventive agent: a promising molecule for fighting cancer. Curr Drug Targets 7:423–442. doi:10.2174/138945006776359331

    Article  PubMed  CAS  Google Scholar 

  13. Busquets S, Ametller E, Fuster G, Olivan M, Raab V, Argiles JM, Lopez-Soriano FJ (2007) Resveratrol, a natural diphenol, reduces metastatic growth in an experimental cancer model. Cancer Lett 245:144–148. doi:10.1016/j.canlet.2005.12.035

    Article  PubMed  CAS  Google Scholar 

  14. Jeong JH, An JY, Kwon YT, Li LY, Lee YJ (2008) Quercetin-induced ubiquitination and down-regulation of Her-2/neu. J Cell Biochem 105:585–595. doi:10.1002/jcb.21859

    Article  PubMed  CAS  Google Scholar 

  15. Yilmaz Y, Toledo RT (2004) Major flavonoids in grape seeds and skins: antioxidant capacity of catechin, epicatechin, and gallic acid. J Agric Food Chem 52:255–260. doi:10.1021/jf030117h

    Article  PubMed  CAS  Google Scholar 

  16. Ebeler SE, Brenneman CA, Kim GS, Jewell WT, Webb MR, Chacon-Rodriguez L, MacDonald EA, Cramer AC, Levi A, Ebeler JD, Islas-Trejo A, Kraus A, Hinrichs SH, Clifford AJ (2002) Dietary catechin delays tumor onset in a transgenic mouse model. Am J Clin Nutr 76:865–872

    PubMed  CAS  Google Scholar 

  17. Gescher AJ, Steward WP (2003) Relationship between mechanisms, bioavailability, and preclinical chemopreventive efficacy of resveratrol: a conundrum. Cancer Epidemiol Biomark Prev 12:953–957

    CAS  Google Scholar 

  18. Soleas GJ, Grass L, Josephy PD, Goldberg DM, Diamandis EP (2002) A comparison of the anticarcinogenic properties of four red wine polyphenols. Clin Biochem 35:119–124. doi:10.1016/S0009-9120(02)00275-8

    Article  PubMed  CAS  Google Scholar 

  19. Meng X, Maliakal P, Lu H, Lee MJ, Yang CS (2004) Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. J Agric Food Chem 52:935–942. doi:10.1021/jf030582e

    Article  PubMed  CAS  Google Scholar 

  20. Manach C, Williamson G, Morand C, Scalbert A, Remesy C (2005) Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 81:230S–242S

    PubMed  CAS  Google Scholar 

  21. Nifli AP, Kampa M, Alexaki VI, Notas G, Castanas E (2005) Polyphenol interaction with the T47D human breast cancer cell line. J Dairy Res 72 Spec No:44–50. doi:10.1017/S0022029905001172

    Article  PubMed  Google Scholar 

  22. Kim YA, Choi BT, Lee YT, Park DI, Rhee SH, Park KY, Choi YH (2004) Resveratrol inhibits cell proliferation and induces apoptosis of human breast carcinoma MCF-7 cells. Oncol Rep 11:441–446

    PubMed  Google Scholar 

  23. Gulati N, Laudet B, Zohrabian VM, Murali R, Jhanwar-Uniyal M (2006) The antiproliferative effect of Quercetin in cancer cells is mediated via inhibition of the PI3K-Akt/PKB pathway. Anticancer Res 26:1177–1181

    PubMed  CAS  Google Scholar 

  24. Whitsett T, Carpenter M, Lamartiniere CA (2006) Resveratrol, but not EGCG, in the diet suppresses DMBA-induced mammary cancer in rats. J Carcinog 5:15–25. doi:10.1186/1477-3163-5-15

    Article  PubMed  Google Scholar 

  25. Garvin S, Ollinger K, Dabrosin C (2006) Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Lett 231:113–122. doi:10.1016/j.canlet.2005.01.031

    Article  PubMed  CAS  Google Scholar 

  26. Dechsupa S, Kothan S, Vergote J, Leger G, Martineau A, Beranger S, Kosanlavit R, Moretti JL, Mankhetkorn S (2007) Quercetin, Siamois 1 and Siamois 2 induce apoptosis in human breast cancer MDA-MB-435 cells xenograft in vivo. Cancer Biol Ther 6:56–61

    PubMed  CAS  Google Scholar 

  27. Cao Y, Cao R, Brakenhielm E (2002) Antiangiogenic mechanisms of diet-derived polyphenols. J Nutr Biochem 13:380–390. doi:10.1016/S0955-2863(02)00204-8

    Article  PubMed  CAS  Google Scholar 

  28. Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506. doi:10.1038/nrd2060

    Article  PubMed  CAS  Google Scholar 

  29. Bhat KP, Lantvit D, Christov K, Mehta RG, Moon RC, Pezzuto JM (2001) Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res 61:7456–7463

    PubMed  CAS  Google Scholar 

  30. Azios NG, Dharmawardhane SF (2005) Resveratrol and estradiol exert disparate effects on cell migration, cell surface actin structures, and focal adhesion assembly in MDA-MB-231 human breast cancer cells. Neoplasia (New York, NY) 7:128–140. doi:10.1593/neo.04346

    CAS  Google Scholar 

  31. Azios NG, Krishnamoorthy L, Harris M, Cubano LA, Cammer M, Dharmawardhane SF (2007) Estrogen and resveratrol regulate Rac and Cdc42 signaling to the actin cytoskeleton of metastatic breast cancer cells. Neoplasia (New York, NY) 9:147–158. doi:10.1593/neo.06778

    CAS  Google Scholar 

  32. Mundy GR (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2:584–593. doi:10.1038/nrc867

    Article  PubMed  CAS  Google Scholar 

  33. Phadke PA, Mercer RR, Harms JF, Jia Y, Frost AR, Jewell JL, Bussard KM, Nelson S, Moore C, Kappes JC, Gay CV, Mastro AM, Welch DR (2006) Kinetics of metastatic breast cancer cell trafficking in bone. Clin Cancer Res 12:1431–1440. doi:10.1158/1078-0432.CCR-05-1806

    Article  PubMed  Google Scholar 

  34. Krajewski S, Krajewska M, Turner BC, Pratt C, Howard B, Zapata JM, Frenkel V, Robertson S, Ionov Y, Yamamoto H, Perucho M, Takayama S, Reed JC (1999) Prognostic significance of apoptosis regulators in breast cancer. Endocr Relat Cancer 6:29–40. doi:10.1677/erc.0.0060029

    Article  PubMed  CAS  Google Scholar 

  35. Fu Z, Tindall DJ (2008) FOXOs, cancer and regulation of apoptosis. Oncogene 27:2312–2319. doi:10.1038/onc.2008.24

    Article  PubMed  CAS  Google Scholar 

  36. Cortes SM, Rodriguez FV, Sanchez PI, Perona R (2008) The role of the NFkappaB signalling pathway in cancer. Clin Transl Oncol 10:143–147. doi:10.1007/s12094-008-0171-3

    Article  Google Scholar 

  37. Welch DR, Harms JF, Mastro AM, Gay CV, Donahue HJ (2003) Breast cancer metastasis to bone: evolving models and research challenges. J Musculoskelet Neuronal Interact 3:30–38

    PubMed  CAS  Google Scholar 

  38. Price JE, Polyzos A, Zhang RD, Daniels LM (1990) Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. Cancer Res 50:717–721

    PubMed  CAS  Google Scholar 

  39. Vantyghem SA, Wilson SM, Postenka CO, Al-Katib W, Tuck AB, Chambers AF (2005) Dietary genistein reduces metastasis in a postsurgical orthotopic breast cancer model. Cancer Res 65:3396–3403

    PubMed  CAS  Google Scholar 

  40. Singh RP, Deep G, Blouin MJ, Pollak MN, Agarwal R (2007) Silibinin suppresses in vivo growth of human prostate carcinoma PC-3 tumor xenograft. Carcinogenesis 28:2567–2574. doi:10.1093/carcin/bgm218

    Article  PubMed  CAS  Google Scholar 

  41. Singh RP, Tyagi A, Sharma G, Mohan S, Agarwal R (2008) Oral silibinin inhibits in vivo human bladder tumor xenograft growth involving down-regulation of survivin. Clin Cancer Res 14:300–308. doi:10.1158/1078-0432.CCR-07-1565

    Article  PubMed  CAS  Google Scholar 

  42. Carlson AL, Hoffmeyer MR, Wall KM, Baugher PJ, Richards-Kortum R, Dharmawardhane SF (2006) In situ analysis of breast cancer progression in murine models using a macroscopic fluorescence imaging system. Lasers Surg Med 38:928–938. doi:10.1002/lsm.20409

    Article  PubMed  Google Scholar 

  43. Lacroix M (2009) MDA-MB-435 cells are from melanoma, not from breast cancer. Cancer Chemother Pharmacol 63:567. doi:10.1007/s00280-008-0776-9

    Article  PubMed  Google Scholar 

  44. Sellappan S, Grijalva R, Zhou X, Yang W, Eli MB, Mills GB, Yu D (2004) Lineage infidelity of MDA-MB-435 cells: expression of melanocyte proteins in a breast cancer cell line. Cancer Res 64:3479–3485. doi:10.1158/0008-5472.CAN-3299-2

    Article  PubMed  CAS  Google Scholar 

  45. Price JE, Zhang RD (1990) Studies of human breast cancer metastasis using nude mice. Cancer Metastasis Rev 8:285–297. doi:10.1007/BF00052605

    Article  PubMed  CAS  Google Scholar 

  46. Frojdo S, Cozzone D, Vidal H, Pirola L (2007) Resveratrol is a class IA phosphoinositide 3-kinase inhibitor. Biochem J 406:511–518. doi:10.1042/BJ20070236

    Article  PubMed  Google Scholar 

  47. Koh SH, Kim SH, Kwon H, Park Y, Kim KS, Song CW, Kim J, Kim MH, Yu HJ, Henkel JS, Jung HK (2003) Epigallocatechin gallate protects nerve growth factor differentiated PC12 cells from oxidative-radical-stress-induced apoptosis through its effect on phosphoinositide 3-kinase/Akt and glycogen synthase kinase-3. Brain Res Mol Brain Res 118:72–81. doi:10.1016/j.molbrainres.2003.07.003

    Article  PubMed  CAS  Google Scholar 

  48. Cantley LC (2004) The role of phosphoinositide 3-kinase in human disease. Harvey Lect 100:103–122

    PubMed  Google Scholar 

  49. Su JL, Yang CY, Zhao M, Kuo ML, Yen ML (2007) Forkhead proteins are critical for bone morphogenetic protein-2 regulation and anti-tumor activity of resveratrol. J Biol Chem 282:19385–19398. doi:10.1074/jbc.M702452200

    Article  PubMed  CAS  Google Scholar 

  50. Terra X, Valls J, Vitrac X, Merrillon JM, Arola L, Ardevol A, Blade C, Fernandez-Larrea J, Pujadas G, Salvado J, Blay M (2007) Grape-seed procyanidins act as antiinflammatory agents in endotoxin-stimulated RAW 264.7 macrophages by inhibiting NFkB signaling pathway. J Agric Food Chem 55:4357–4365. doi:10.1021/jf0633185

    Article  PubMed  CAS  Google Scholar 

  51. Pozo-Guisado E, Merino JM, Mulero-Navarro S, Lorenzo-Benayas MJ, Centeno F, Alvarez-Barrientos A, Salguero PM (2005) Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB. Int J Cancer 115:74–84. doi:10.1002/ijc.20856

    Article  PubMed  CAS  Google Scholar 

  52. Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, Nair AS, Shishodia S, Aggarwal BB (2007) Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood 109:2293–2302. doi:10.1182/blood-2006-02-003988

    Article  PubMed  CAS  Google Scholar 

  53. Garcia-Mediavilla V, Crespo I, Collado PS, Esteller A, Sanchez-Campos S, Tunon MJ, Gonzalez-Gallego J (2007) The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur J Pharmacol 557:221–229. doi:10.1016/j.ejphar.2006.11.014

    Article  PubMed  CAS  Google Scholar 

  54. Wolska A, Lech-Marańda E, Robak T (2008) Toll-like receptors and their role in carcinogenesis and anti-tumor treatment. Cell Mol Biol Lett. doi:10.2478/s11658-008-0048-z

  55. Fukao T, Koyasu S (2003) PI3K and negative regulation of TLR signaling. Trends Immunol 24:358–363. doi:10.1016/S1471-4906(03)00139-X

    Article  PubMed  CAS  Google Scholar 

  56. Martinez C, Vicente V, Yanez J, Alcaraz M, Castells MT, Canteras M, Benavente-Garcia O, Castillo J (2005) The effect of the flavonoid diosmin, grape seed extract and red wine on the pulmonary metastatic B16F10 melanoma. Histol Histopathol 20:1121–1129

    PubMed  CAS  Google Scholar 

  57. Singh RP, Tyagi AK, Dhanalakshmi S, Agarwal R, Agarwal C (2004) Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3. Int J Cancer 108:733–740. doi:10.1002/ijc.11620

    Article  PubMed  CAS  Google Scholar 

  58. Kim H, Hall P, Smith M, Kirk M, Prasain JK, Barnes S, Grubbs C (2004) Chemoprevention by grape seed extract and genistein in carcinogen-induced mammary cancer in rats is diet dependent. J Nutr 134:3445S–3452S

    PubMed  CAS  Google Scholar 

  59. Morre DM, Morre DJ (2006) Anticancer activity of grape and grape skin extracts alone and combined with green tea infusions. Cancer Lett 238:202–209. doi:10.1016/j.canlet.2005.07.011

    Article  PubMed  CAS  Google Scholar 

  60. Kapoor P, Suva LJ, Welch DR, Donahue HJ (2008) Osteoprotegrin and the bone homing and colonization potential of breast cancer cells. J Cell Biochem 103:30–41. doi:10.1002/jcb.21382

    Article  PubMed  CAS  Google Scholar 

  61. Ignatoski KM, Escara-Wilke JF, Dai JL, Lui A, Dougall W, Daignault S, Yao Z, Zhang J, Day ML, Sargent EE, Keller ET (2008) RANKL inhibition is an effective adjuvant for docetaxel in a prostate cancer bone metastases model. Prostate 68:820–829. doi:10.1002/pros.20744

    Article  PubMed  CAS  Google Scholar 

  62. Cicek M, Oursler MJ (2006) Breast cancer bone metastasis and current small therapeutics. Cancer Metastasis Rev 25:635–644. doi:10.1007/s10555-006-9035-x

    Article  PubMed  CAS  Google Scholar 

  63. Meir T, Dror R, Yu X, Qian J, Simon I, Pe’er J, Chowers I (2007) Molecular characteristics of liver metastases from uveal melanoma. Invest Ophthalmol Vis Sci 48:4890–4896. doi:10.1167/iovs.07-0215

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge the excellent technical assistance of Alexander Schlachterman, Felix Valle, and Alina De La Mota-Peynado with the animal protocols. This research was supported by grant numbers AICR IIG 03-31-06 and DoD/BCRP W81XWH-07-1-0330 to SD; DoD/BCRP W81XWH-08-01-0258 to LCP; NCCR/NIH 2G12RR003035, S06GM050695, and G11HD052352 to UCC; and NIH/RCMI G12-RR03051 and MBRS-RISE 5R25GM061838-08 to UPR-MSC. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCRR, NICHD, NIGMS or the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, PR, USA

    Linette Castillo-Pichardo & Suranganie Dharmawardhane

  2. Department of Anatomy and Cell Biology, School of Medicine, Universidad Central del Caribe, P.O. Box 60327, Bayamón, PR, 00960-6032, USA

    Michelle M. Martínez-Montemayor, Joel E. Martínez, Kristin M. Wall, Luis A. Cubano & Suranganie Dharmawardhane

Authors
  1. Linette Castillo-Pichardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michelle M. Martínez-Montemayor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joel E. Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kristin M. Wall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luis A. Cubano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Suranganie Dharmawardhane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suranganie Dharmawardhane.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Castillo-Pichardo, L., Martínez-Montemayor, M.M., Martínez, J.E. et al. Inhibition of mammary tumor growth and metastases to bone and liver by dietary grape polyphenols. Clin Exp Metastasis 26, 505–516 (2009). https://doi.org/10.1007/s10585-009-9250-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-009-9250-2

Keywords

Search

Navigation