Skip to main content
PMC home page
Protein & Cell logoLink to Protein & Cell
. 2011 Jul 12;2(6):507–516. doi: 10.1007/s13238-011-1056-8

Naringenin reduces lung metastasis in a breast cancer resection model

Lei Qin 1,2, Lingtao Jin 1, Linlin Lu 1, Xiaoyan Lu 3, Chunling Zhang 1, Fayun Zhang 1, Wei Liang 1,✉
PMCID: PMC4875175  PMID: 21748601

Abstract

Metastasis is the main cause of death in cancer patients. To improve the outcomes of patients undergoing a surgery, new adjuvant therapies that can effectively inhibit metastases have to be developed. Studies have shown that flavonoid naringenin, a natural product that is mainly present in grapes and citrus, may contribute to cancer prevention. It has many advantages compared to traditional chemotherapeutic drugs, such as low toxicity. To determine whether naringenin can also inhibit metastases, a breast cancer resection model that mimics clinical situations was established. We found that orally administered naringenin significantly decreased the number of metastatic tumor cells in the lung and extended the life span of tumor resected mice. Flow cytometry analysis revealed that T cells displayed enhanced antitumor activity in naringenin treated mice, with an increased proportion of IFN-γ and IL-2 expressing T cells. In vitro studies further demonstrated that relief of immunosuppression caused by regulatory T cells might be the fundamental mechanism of metastasis inhibition by naringenin. These results indicate that orally administered naringenin can inhibit the outgrowth of metastases after surgery via regulating host immunity. Thus, naringenin can be an ideal surgical adjuvant therapy for breast cancer patients.

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s13238-011-1056-8 and is accessible for authorized users.

Keywords: naringenin, breast cancer, surgery, metastasis, immunosuppression, Tregs

Electronic supplementary material

13238_2011_1056_MOESM1_ESM.pdf (148.2KB, pdf)

Supplementary material, approximately 148 KB.

Footnotes

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s13238-011-1056-8 and is accessible for authorized users.

References

  1. Ben-Eliyahu S. The promotion of tumor metastasis by surgery and stress: immunological basis and implications for psychoneuroimmunology. Brain Behav Immun. 2003;17:S27–S36. doi: 10.1016/S0889-1591(02)00063-6. [DOI] [PubMed] [Google Scholar]
  2. Beyer M., Schultze J.L. Regulatory T cells in cancer. Blood. 2006;108:804–811. doi: 10.1182/blood-2006-02-002774. [DOI] [PubMed] [Google Scholar]
  3. Bindea G., Mlecnik B., Fridman W.H., Pages F., Galon J. Natural immunity to cancer in humans. Curr Opin Immunol. 2010;22:215–222. doi: 10.1016/j.coi.2010.02.006. [DOI] [PubMed] [Google Scholar]
  4. Boomsma M.F., Garssen B., Slot E., Berbee M., Berkhof J., Meezenbroek Ede J., Slieker W., Visser A., Meijer S., Beelen R.H. Breast cancer surgery-induced immunomodulation. J Surg Oncol. 2010;102:640–648. doi: 10.1002/jso.21662. [DOI] [PubMed] [Google Scholar]
  5. Brandacher G., Winkler C., Schroecksnadel K., Margreiter R., Fuchs D. Antitumoral activity of interferon-gamma involved in impaired immune function in cancer patients. Curr Drug Metab. 2006;7:599–612. doi: 10.2174/138920006778017768. [DOI] [PubMed] [Google Scholar]
  6. Brune I.B., Wilke W., Hensler T., Holzmann B., Siewert J.R. Downregulation of T helper type 1 immune response and altered pro-inflammatory and anti-inflammatory T cell cytokine balance following conventional but not laparoscopic surgery. Am J Surg. 1999;177:55–60. doi: 10.1016/S0002-9610(98)00299-2. [DOI] [PubMed] [Google Scholar]
  7. Chen L., Huang T.G., Meseck M., Mandeli J., Fallon J., Woo S.L. Rejection of metastatic 4T1 breast cancer by attenuation of Treg cells in combination with immune stimulation. Mol Ther. 2007;15:2194–2202. doi: 10.1038/sj.mt.6300310. [DOI] [PubMed] [Google Scholar]
  8. Chen W.J., Konkel J.E. TGF-beta and ‘Adaptive’ Foxp3(+) Regulatory T cells. J Mol Cell Biol. 2010;2:30–36. doi: 10.1093/jmcb/mjp004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chiang J.Y., Jang I.K., Hodes R., Gu H. Ablation of Cblb provides protection against transplanted and spontaneous tumors. J Clin Invest. 2007;117:1029–1036. doi: 10.1172/JCI29472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Coffelt S.B., Hughes R., Lewis C.E. Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta. 2009;1796:11–18. doi: 10.1016/j.bbcan.2009.02.004. [DOI] [PubMed] [Google Scholar]
  11. Coughlin S.S., Ekwueme D.U. Breast cancer as a global health concern. Cancer Epidemiol. 2009;33:315–318. doi: 10.1016/j.canep.2009.10.003. [DOI] [PubMed] [Google Scholar]
  12. Du G., Jin L., Han X., Song Z., Zhang H., Liang W. Naringenin: a potential immunomodulator for inhibiting lung fibrosis and metastasis. Cancer Res. 2009;69:3205–3212. doi: 10.1158/0008-5472.CAN-08-3393. [DOI] [PubMed] [Google Scholar]
  13. duPre S.A., Redelman D., Hunter K.W., Jr. Microenvironment of the murine mammary carcinoma 4T1: endogenous IFNgamma affects tumor phenotype, growth, and metastasis. Exp Mol Pathol. 2008;85:174–188. doi: 10.1016/j.yexmp.2008.05.002. [DOI] [PubMed] [Google Scholar]
  14. Faist E., Kupper T.S., Baker C.C., Chaudry I.H., Dwyer J., Baue A.E. Depression of Cellular-Immunity after Major Injury - Its Association with Posttraumatic Complications and Its Reversal with Immunomodulation. Arch Surg-Chicago. 1986;121:1000–1005. doi: 10.1001/archsurg.1986.01400090026004. [DOI] [PubMed] [Google Scholar]
  15. Fang F., Tang Y., Gao Z., Xu Q. A novel regulatory mechanism of naringenin through inhibition of T lymphocyte function in contact hypersensitivity suppression. Biochem Biophys Res Commun. 2010;397:163–169. doi: 10.1016/j.bbrc.2010.05.065. [DOI] [PubMed] [Google Scholar]
  16. Gabrilovich D.I., Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–174. doi: 10.1038/nri2506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hogan B.V., Peter M.B., Shenoy H.G., Horgan K., Hughes T.A. Surgery induced immunosuppression. Surg-J R Coll Surg E. 2011;9:38–43. doi: 10.1016/j.surge.2010.07.011. [DOI] [PubMed] [Google Scholar]
  18. James M.A., Lu Y., Liu Y., Vikis H.G., You M. RGS17, an overexpressed gene in human lung and prostate cancer, induces tumor cell proliferation through the cyclic AMP-PKA-CREB pathway. Cancer Res. 2009;69:2108–2116. doi: 10.1158/0008-5472.CAN-08-3495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jemal A., Siegel R., Xu J., Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300. doi: 10.3322/caac.20073. [DOI] [PubMed] [Google Scholar]
  20. Kanno S., Tomizawa A., Hiura T., Osanai Y., Shouji A., Ujibe M., Ohtake T., Kimura K., Ishikawa M. Inhibitory effects of naringenin on tumor growth in human cancer cell lines and sarcoma S-180-implanted mice. Biol Pharm Bull. 2005;28:527–530. doi: 10.1248/bpb.28.527. [DOI] [PubMed] [Google Scholar]
  21. Ko K., Yamazaki S., Nakamura K., Nishioka T., Hirota K., Yamaguchi T., Shimizu J., Nomura T., Chiba T., Sakaguchi S. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3 + CD25 + CD4 + regulatory T cells. J Exp Med. 2005;202:885–891. doi: 10.1084/jem.20050940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kong L.Y., Wei J., Sharma A.K., Barr J., Abou-Ghazal M.K., Fokt I., Weinberg J., Rao G., Grimm E., Priebe W., et al. A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells. Cancer Immunol Immunother. 2009;58:1023–1032. doi: 10.1007/s00262-008-0618-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Le Marchand L., Murphy S.P., Hankin J.H., Wilkens L.R., Kolonel L.N. Intake of flavonoids and lung cancer. J Natl Cancer Inst. 2000;92:154–160. doi: 10.1093/jnci/92.2.154. [DOI] [PubMed] [Google Scholar]
  24. Liyanage U.K., Moore T.T., Joo H.G., Tanaka Y., Herrmann V., Doherty G., Drebin J.A., Strasberg S.M., Eberlein T.J., Goedegebuure P.S., et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169:2756–2761. doi: 10.4049/jimmunol.169.5.2756. [DOI] [PubMed] [Google Scholar]
  25. Lohr F., Hu K., Haroon Z., Samulski T.V., Huang Q., Beaty J., Dewhirst M.W., Li C.Y. Combination treatment of murine tumors by adenovirus-mediated local B7/IL12 immunotherapy and radiotherapy. Mol Ther. 2000;2:195–203. doi: 10.1006/mthe.2000.0114. [DOI] [PubMed] [Google Scholar]
  26. Marigo I., Dolcetti L., Serafini P., Zanovello P., Bronte V. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev. 2008;222:162–179. doi: 10.1111/j.1600-065X.2008.00602.x. [DOI] [PubMed] [Google Scholar]
  27. Markiewicz D.A., Schultz D.J., Haas J.A., Harris E.E., Fox K.R., Glick J.H., Solin L.J. The effects of sequence and type of chemotherapy and radiation therapy on cosmesis and complications after breast conservation therapy. Int J Radiat Oncol Biol Phys. 1996;35:661–668. doi: 10.1016/0360-3016(96)00171-X. [DOI] [PubMed] [Google Scholar]
  28. McCahill L.E., Privette A., James T., Sheehey-Jones J., Ratliff J., Majercik D., Krag D.N., Stanley M., Harlow S. Quality measures for breast cancer surgery: initial validation of feasibility and assessment of variation among surgeons. Arch Surg. 2009;144:455–462. doi: 10.1001/archsurg.2009.56. [DOI] [PubMed] [Google Scholar]
  29. Ogawa K., Hirai M., Katsube T., Murayama H., Hamaguchi K., Shimakawa T., Naritake Y., Hosokawa T., Kajiwara T. Suppression of cellular immunity by surgical stress. Surgery. 2000;127:329–336. doi: 10.1067/msy.2000.103498. [DOI] [PubMed] [Google Scholar]
  30. Ortiz-Andrade R.R., Sanchez-Salgado J.C., Navarrete-Vazquez G., Webster S.P., Binnie M., Garcia-Jimenez S., Leon-Rivera I., Cigarroa-Vazquez P., Villalobos-Molina R., Estrada-Soto S. Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation. Diabetes Obes Metab. 2008;10:1097–1104. doi: 10.1111/j.1463-1326.2008.00869.x. [DOI] [PubMed] [Google Scholar]
  31. Page G.G., Ben-Eliyahu S. Increased surgery-induced metastasis and suppressed natural killer cell activity during proestrus/estrus in rats. Breast Cancer Res Treat. 1997;45:159–167. doi: 10.1023/A:1005826403235. [DOI] [PubMed] [Google Scholar]
  32. Pulaski, B.A., and Ostrand-Rosenberg, S. (2001). Mouse 4T1 breast tumor model. Curr Protoc Immunol Chapter 20, Unit 20.2. [DOI] [PubMed]
  33. Pulaski B.A., Terman D.S., Khan S., Muller E., Ostrand-Rosenberg S. Cooperativity of Staphylococcal aureus enterotoxin B superantigen, major histocompatibility complex class II, and CD80 for immunotherapy of advanced spontaneous metastases in a clinically relevant postoperative mouse breast cancer model. Cancer Res. 2000;60:2710–2715. [PubMed] [Google Scholar]
  34. Rosenberg S.A. Progress in human tumour immunology and immunotherapy. Nature. 2001;411:380–384. doi: 10.1038/35077246. [DOI] [PubMed] [Google Scholar]
  35. Salo M. Effects of anaesthesia and surgery on the immune response. Acta Anaesthesiol Scand. 1992;36:201–220. doi: 10.1111/j.1399-6576.1992.tb03452.x. [DOI] [PubMed] [Google Scholar]
  36. Shafir M., Bekesi J.G., Papatestas A., Slater G., Aufses A.H. Preoperative and Postoperative Immunological Evaluation of Patients with Colorectal-Cancer. Cancer. 1980;46:700–705. doi: 10.1002/1097-0142(19800815)46:4<700::AID-CNCR2820460411>3.0.CO;2-Z. [DOI] [PubMed] [Google Scholar]
  37. Shenkier T., Weir L., Levine M., Olivotto I., Whelan T., Reyno L. Clinical practice guidelines for the care and treatment of breast cancer: 15. Treatment for women with stage III or locally advanced breast cancer. CMAJ. 2004;170:983–994. doi: 10.1503/cmaj.1030944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. So F.V., Guthrie N., Chambers A.F., Moussa M., Carroll K.K. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer. 1996;26:167–181. doi: 10.1080/01635589609514473. [DOI] [PubMed] [Google Scholar]
  39. Townsend S.E., Allison J.P. Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells. Science. 1993;259:368–370. doi: 10.1126/science.7678351. [DOI] [PubMed] [Google Scholar]
  40. van der Bij G.J., Oosterling S.J., Bogels M., Bhoelan F., Fluitsma D.M., Beelen R.H., Meijer S., van Egmond M. Blocking alpha2 integrins on rat CC531s colon carcinoma cells prevents operation-induced augmentation of liver metastases outgrowth. Hepatology. 2008;47:532–543. doi: 10.1002/hep.22013. [DOI] [PubMed] [Google Scholar]
  41. Whiteside T.L. Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. Semin Cancer Biol. 2006;16:3–15. doi: 10.1016/j.semcancer.2005.07.008. [DOI] [PubMed] [Google Scholar]
  42. Yang Y., Xu Y., Xia T., Chen F., Zhang C., Liang W., Lai L., Fang X. A single-molecule study of the inhibition effect of Naringenin on transforming growth factor-beta ligand-receptor binding. Chem Commun (Camb) 2011;47:5440–5442. doi: 10.1039/c1cc10778j. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

13238_2011_1056_MOESM1_ESM.pdf (148.2KB, pdf)

Supplementary material, approximately 148 KB.

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES