Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway

Abstract

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is an ingredient of chili peppers with inhibitory effects against cancer cells of different origin. We examined the activity of capsaicin on breast cancer cells in vitro and in vivo. The drug potently inhibited growth of ER-positive (MCF-7, T47D, BT-474) and ER-negative (SKBR-3, MDA-MB231) breast cancer cell lines, which was associated with G0/G1 cell-cycle arrest, increased levels of apoptosis and reduced protein expression of human epidermal growth factor receptor (EGFR), HER-2, activated extracellular-regulated kinase (ERK) and cyclin D1. In contrast, cell-cycle regulator p27KIP1, caspase activity as well as poly-ADP ribose polymerase (PARP) cleavage were increased. Notably, capsaicin blocked breast cancer cell migration in vitro and decreased by 50% the size of MDA-MB231 breast cancer tumors growing orthotopically in immunodeficient mice without noticeable drug side effects. in vivo activation of ERK was clearly decreased, as well as expression of HER-2 and cyclin D1, whereas caspase activity and PARP cleavage products were increased in tumors of drug-treated mice. Besides, capsaicin potently inhibited the development of pre-neoplastic breast lesions by up to 80% without evidence of toxicity. Our data indicate that capsaicin is a novel modulator of the EGFR/HER-2 pathway in both ER-positive and -negative breast cancer cells with a potential role in the treatment and prevention of human breast cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Athanasiou A, Smith PA, Vakilpour S, Kumaran NM, Turner AE, Bagiokou D et al. (2007). Vanilloid receptor agonists and antagonists are mitochondrial inhibitors: how vanilloids cause non-vanilloid receptor mediated cell death. Biochem Biophys Res Commun 354: 50–55.

    Article  CAS  Google Scholar 

  • Carraway III KL, Sweeney C . (2006). Co-opted integrin signaling in ErbB2-induced mammary tumor progression. Cancer Cell 10: 93–95.

    Article  CAS  Google Scholar 

  • Chen FL, Wenle Xia W, Spector NL . (2008). Acquired resistance to small molecule ErbB2 tyrosine kinase inhibitors. Clin Cancer Res 14: 6730.

    Article  CAS  Google Scholar 

  • Council of Europe. (2001). Committee of Experts on Flavoring Substances. 48th Meeting Strasbourg, 2–6-April 2001. Document RD 4/2-52. Datasheet on Capsaicin.

  • Eckert LB, Repasky GA, Ulkü AS, McFall A, Zhou H, Sartor CI et al. (2004). Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis. Cancer Res 64: 4585–4592.

    Article  CAS  Google Scholar 

  • Fukazawa H, Noguchi K, Murakami Y, Yoshimasa Uehara Y . (2002). Mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitors restore anoikis sensitivity in human breast cancer cell lines with a constitutively activated extracellular-regulated kinase (ERK) pathway. Mol Cancer Ther 1: 303–309.

    CAS  PubMed  Google Scholar 

  • Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN . (2007). Overview of resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol 608: 1–22.

    Article  CAS  Google Scholar 

  • Hail N, Lotan R . (2002). Examining the role of mitochondrial respiration in vanilloid-induced apoptosis. J Natl Cancer Inst 94: 1281–1292.

    Article  CAS  Google Scholar 

  • Ito K, Nakazato T, Yamato K, Miyakawa Y, Yamada T, Hozumi N et al. (2004). Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress: implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species. Cancer Res 64: 1071–1078.

    Article  CAS  Google Scholar 

  • Johnson Jr W . (2007). Final report on the safety assessment of capsicum annuum extract, capsicum annuum fruit extract, capsicum annuum resin, capsicum annuum fruit powder, capsicum frutescens fruit, capsicum frutescens fruit extract, capsicum frutescens resin, and capsaicin. Int J Toxicol 26: 3–106.

    Google Scholar 

  • Jung MY, Kang HJ, Moon A . (2001). Capsaicin-induced apoptosis in SK-Hep-1 hepatocarcinoma cells involves Bcl-2 downregulation and capsase-3 activation. Cancer Lett 165: 139–145.

    Article  CAS  Google Scholar 

  • Kawada M, Yamagoe S, Murakami Y, Suzuki K, Mizuno S, Uehara Y . (1997). Induction of p27Kip1 degradation and anchorage independence by Ras through the MAP kinase signaling pathway. Oncogene 15: 629–637.

    Article  CAS  Google Scholar 

  • Kim CS, Park WH, Park JY, Kang JH, Kim MO, Kawada T et al. (2004). Capsaicin, a spicy component of hot pepper, induces apoptosis by activation of the peroxisome proliferator-activated receptor gamma in HT-29 human colon cancer cells. J Med Food 7: 267–273.

    Article  CAS  Google Scholar 

  • Korkaya H, Paulson A, Iovino F, Wicha MS . (2008). HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 27: 6120–6130.

    Article  CAS  Google Scholar 

  • Krueger JS, Keshamouni VG, Atanaskova N, Reddy KB. (2001). Temporal and quantitative regulation of mitogen-activated protein kinase (MAPK) modulates cell motility and invasion. Oncogene 20: 4209–4218.

    Article  CAS  Google Scholar 

  • Kumagai T, O’Kelly J, Said JW, Koeffler HP . (2003). Vitamin D2 analog 19-nor-1,25-dihydroxyvitamin D2: antitumor activity against leukemia, myeloma, and colon cancer cells. J Natl Cancer Inst 95: 896–905.

    Article  CAS  Google Scholar 

  • Lavoie JN, Rivard N, L’Allemain G, Pouysségur J . (1996). A temporal and biochemical link between growth factor-activated MAP kinases, cyclin D1 induction and cell cycle entry. Prog Cell Cycle Res 2: 49–58.

    Article  CAS  Google Scholar 

  • Lo YC, Yang YC, Wu IC, Kuo FC, Liu CM, Wang HW et al. (2005). Capsaicin-induced cell death in a human gastric adenocarcinoma cell line. World J Gastroenterol 11: 6254–6257.

    Article  CAS  Google Scholar 

  • Magkou C, Nakopoulou L, Zoubouli C, Karali K, Theohari I, Bakarakos P et al. (2008). Expression of the epidermal growth factor receptor (EGFR) and the phosphorylated EGFR in invasive breast carcinomas. Breast Cancer Res 10: R49.

    Article  Google Scholar 

  • Mehta RG, Bhat KP, Hawthorne ME, Kopelovich L, Mehta RR, Christov K et al. (2001). Induction of atypical hyperplasia in mouse mammary gland organ culture. J Natl Cancer Inst 93: 1103–1106.

    Article  CAS  Google Scholar 

  • Mehta RG, Williamson E, Patel M, Koeffler HP . (2000). PPARγ ligand and retinoids prevent pre-neoplastic mammary lesions. J Natl Cancer Inst 92: 418–423.

    Article  CAS  Google Scholar 

  • Ménard S, Pupa SM, Campiglio M, Tagliabue E . (2003). Biologic and therapeutic role of HER2 in cancer. Oncogene 22: 6570–6578.

    Article  Google Scholar 

  • Mendelsohn J, Baselga J . (2000). The EGF receptor family as targets for cancer therapy. Oncogene 19: 6550–6565.

    Article  CAS  Google Scholar 

  • Mendelsohn J, Baselga J . (2003). Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21: 2787–2799.

    Article  CAS  Google Scholar 

  • Monsereenusorn Y, Kongsamut S, Pezella PD . (1982). Capsaicin: a literature survey. Crit Rev Toxicol 10: 321–339.

    Article  CAS  Google Scholar 

  • Montgomery RB, Makary E, Schiffman K, Goodell V, Disis ML . (2005). Endogenous anti-HER2 antibodies block HER2 phosphorylation and signaling through extracellular signal-regulated kinase. Cancer Res 65: 650–656.

    CAS  PubMed  Google Scholar 

  • Mori A, Lehmann S, O’Kelly J, Kumagai T, Desmond JC, Pervan M et al. (2006). Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer Res 66: 3222–3229.

    Article  CAS  Google Scholar 

  • Morre DJ, Chueh PJ, Morre DM . (1995). Capsaicin inhibits preferentially the NADH oxidase and growth of transformed cells in culture. Proc Natl Acad Sci USA 92: 1831–1835.

    Article  CAS  Google Scholar 

  • Morris GJ, Mitchell EP . (2008). Higher incidence of aggressive breast cancers in African-American women: a review. J Natl Med Assoc 100: 698–702.

    Article  Google Scholar 

  • Rock E, DeMichele A . (2003). Nutritional approaches to late toxicities of adjuvant chemotherapy in breast cancer survivors. J Nutr 133: 3785–3793.

    Article  Google Scholar 

  • Sánchez AM, Sánchez MG, Malagarie-Cazenave S, Olea N, Díaz-Laviada I . (2006). Induction of apoptosis in prostate tumor PC-3 cells and inhibition of xenograft prostate tumor growth by the vanilloid capsaicin. Apoptosis 11: 89–99.

    Article  Google Scholar 

  • Scaltriti M, Baselga J . (2006). The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 12: 5268–5272.

    Article  CAS  Google Scholar 

  • Schafer JM, Bentrem DJ, Takei H, Gajdos C, Badve S, Jordan VC . (2002). A mechanism of drug resistance to tamoxifen in breast cancer. J Steroid Biochem Mol Biol 83: 75–83.

    Article  CAS  Google Scholar 

  • Sivaraman VS, Wang H, Nuovo GJ, Malbon CC . (1997). Hyperexpression of mitogen-activated protein kinase in human breast cancer. J Clin Invest 99: 1478–1483.

    Article  CAS  Google Scholar 

  • Solit DB, Zheng FF, Drobnjak M, Münster PN, Higgins B, Verbel D et al. (2002). 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res 8: 986–993.

    CAS  PubMed  Google Scholar 

  • Taik-koo Y . (1999). Update from Asia: Asian studies on cancer chemoprevention. Ann NY Acad Sci 889: 157–192.

    Article  Google Scholar 

  • Tuoya, Baba N, Shimoishi Y, Murata Y, Tada M, Koseki M et al. (2006). Apoptosis induction by dohevanil, a DHA substitutive analog of capsaicin, in MCF-7 cells. Life Sci 78: 1515–1519.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

NH Thoennissen's work was supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany (TH 1438/1-1); B Karlan by the Woman Cancer Institute of Cedars-Sinai Medical Center, Los Angeles, CA, USA and GB Iwanski by the Jung-Stiftung für Wissenschaft und Forschung, Hamburg, Germany. HP Koeffler is the holder of the Mark Goodson endowed Chair in Oncology Research and is a member of the Jonsson Cancer and Molecular Biology Institute, UCLA, Los Angeles, CA, USA.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N H Thoennissen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thoennissen, N., O'Kelly, J., Lu, D. et al. Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway. Oncogene 29, 285–296 (2010). https://doi.org/10.1038/onc.2009.335

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.335

Keywords

This article is cited by

Search

Quick links