Skip to main content

Advertisement

SpringerLink
Log in

Synergistic effect between celecoxib and luteolin is dependent on estrogen receptor in human breast cancer cells

  • Research Article
  • Published:
Tumor Biology

Abstract

The anti-cancer effects of celecoxib and luteolin are well known. Although our previous study demonstrated that the combination of celecoxib and luteolin synergistically inhibits breast tumor growth compared with each of the treatments alone, we did not uncover the molecular mechanisms of these effects. The aims of our present study were to compare the effects of a celecoxib and luteolin combination treatment in four different human breast cell lines and to determine the mechanisms of action in vitro and in vivo. The synergistic effects of a celecoxib and luteolin combination treatment yielded significantly greater cell growth inhibition in all four breast cancer cell lines compared with the single agents alone. In particular, combined celecoxib and luteolin treatment significantly decreased the growth of MDA-MB-231 cancer cells in vivo compared with either agent alone. The celecoxib and luteolin combination treatment induced synergistic effects via Akt inactivation and extracellular signal-regulated kinase (ERK) signaling inhibition in MCF-7 and MCF7/HER18 cells and via Akt inactivation and ERK signaling activation in MDA-MB-231 and SkBr3 cells. These results demonstrate the synergistic anti-tumor effect of the celecoxib and luteolin combination treatment in different four breast cancer cell lines, thus introducing the possibility of this combination as a new treatment modality.

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

Similar content being viewed by others

References

  1. Basu GD, Pathangey LB, Tinder TL, Lagioia M, Gendler SJ, Mukherjee P. Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer. Mol Cancer Res. 2004;2:632–42.

    CAS  PubMed  Google Scholar 

  2. Kulp SK, Yang YT, Hung CC, Chen KF, Lai JP, Tseng PH, et al. 3-phosphoinositide-dependent protein kinase-1/Akt signaling represents a major cyclooxygenase-2-independent target for celecoxib in prostate cancer cells. Cancer Res. 2004;64:1444–51.

    Article  CAS  PubMed  Google Scholar 

  3. Suh YJ, Chada S, McKenzie T, Liu Y, Swisher SG, Lucci A, et al. Synergistic tumoricidal effect between celecoxib and adenoviral-mediated delivery of mda-7 in human breast cancer cells. Surgery. 2005;138:422–30.

    Article  PubMed  Google Scholar 

  4. Barnes NL, Warnberg F, Farnie G, White D, Jiang W, Anderson E, et al. Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer. Br J Cancer. 2007;96:575–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ghosh N, Chaki R, Mandal V, Mandal SC. COX-2 as a target for cancer chemotherapy. Pharmacol Rep. 2010;62:233–44.

    Article  CAS  PubMed  Google Scholar 

  6. Sheng H, Shao J, Dixon DA, Williams CS, Prescott SM, DuBois RN, et al. Transforming growth factor-beta1 enhances Ha-ras-induced expression of cyclooxygenase-2 in intestinal epithelial cells via stabilization of mRNA. J Biol Chem. 2000;275:6628–35.

    Article  CAS  PubMed  Google Scholar 

  7. Sheng H, Williams CS, Shao J, Liang P, DuBois RN, Beauchamp RD. Induction of cyclooxygenase-2 by activated Ha-ras oncogene in Rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway. J Biol Chem. 1998;273:22120–7.

    Article  CAS  PubMed  Google Scholar 

  8. Sheng H, Shao J, Dubois RN. K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1. Cancer Res. 2001;61:2670–5.

    CAS  PubMed  Google Scholar 

  9. Arico S, Pattingre S, Bauvy C, Gane P, Barbat A, Codogno P, et al. Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line. J Biol Chem. 2002;277:27613–21.

    Article  CAS  PubMed  Google Scholar 

  10. Harris RE, Beebe-Donk J, Alshafie GA. Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer. 2006;6:27.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Brasky TM, Bonner MR, Moysich KB, Ambrosone CB, Nie J, Tao MH, et al. Non-steroidal anti-inflammatory drug (NSAID) use and breast cancer risk in the Western New York Exposures and Breast Cancer (WEB) Study. Cancer Causes Control. 2010;21:1503–12.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther. 2001;90:157–77.

    Article  CAS  PubMed  Google Scholar 

  13. Lin Y, Shi R, Wang X, Shen HM. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets. 2008;8:634–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Falandry C, Canney PA, Freyer G, Dirix LY. Role of combination therapy with aromatase and cyclooxygenase-2 inhibitors in patients with metastatic breast cancer. Ann Oncol. 2009;20:615–20.

    Article  CAS  PubMed  Google Scholar 

  15. Canney PA, Machin MA, Curto J. A feasibility study of the efficacy and tolerability of the combination of Exemestane with the COX-2 inhibitor celecoxib in post-menopausal patients with advanced breast cancer. Eur J Cancer. 2006;42:2751–6.

    Article  CAS  PubMed  Google Scholar 

  16. Mustafa A, Kruger WD. Suppression of tumor formation by a cyclooxygenase-2 inhibitor and a peroxisome proliferator-activated receptor gamma agonist in an in vivo mouse model of spontaneous breast cancer. Clin Cancer Res. 2008;14:4935–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jeon YW, Suh YJ. Synergistic apoptotic effect of celecoxib and luteolin on breast cancer cells. Oncol Rep. 2013;29:819–25.

    CAS  PubMed  Google Scholar 

  18. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.

    Article  CAS  PubMed  Google Scholar 

  19. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869–74.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55.

    Article  CAS  PubMed  Google Scholar 

  21. Graves JD, Draves KE, Craxton A, Saklatvala J, Krebs EG, Clark EA. Involvement of stress-activated protein kinase and p38 mitogen-activated protein kinase in mIgM-induced apoptosis of human B lymphocytes. Proc Natl Acad Sci U S A. 1996;93:13814–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Brenner B, Koppenhoefer U, Weinstock C, Linderkamp O, Lang F, Gulbins E. Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153. J Biol Chem. 1997;272:22173–81.

    Article  CAS  PubMed  Google Scholar 

  23. Tang D, Wu D, Hirao A, Lahti JM, Liu L, Mazza B, et al. ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53. J Biol Chem. 2002;277:12710–7.

    Article  CAS  PubMed  Google Scholar 

  24. Han DH, Denison MS, Tachibana H, Yamada K. Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids. Biosci Biotechnol Biochem. 2002;66:1479–87.

    Article  CAS  PubMed  Google Scholar 

  25. Chiu FL, Lin JK. Downregulation of androgen receptor expression by luteolin causes inhibition of cell proliferation and induction of apoptosis in human prostate cancer cells and xenografts. Prostate. 2008;68:61–71.

    Article  CAS  PubMed  Google Scholar 

  26. Holland MB, Roy D. Estrogen-induced cell proliferation and differentiation in the mammary gland of the female Noble rat. Carcinogenesis. 1995;16:1955–61.

    Article  CAS  PubMed  Google Scholar 

  27. Saini KS, Loi S, de Azambuja E, Metzger-Filho O, Saini ML, Ignatiadis M, et al. Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer. Cancer Treat Rev. 2013;39:935–46.

    Article  CAS  PubMed  Google Scholar 

  28. Chiang CT, Way TD, Lin JK. Sensitizing HER2-overexpressing cancer cells to luteolin-induced apoptosis through suppressing p21(WAF1/CIP1) expression with rapamycin. Mol Cancer Ther. 2007;6:2127–38.

    Article  CAS  PubMed  Google Scholar 

  29. Fang J, Zhou Q, Shi XL, Jiang BH. Luteolin inhibits insulin-like growth factor 1 receptor signaling in prostate cancer cells. Carcinogenesis. 2007;28:713–23.

    Article  CAS  PubMed  Google Scholar 

  30. Chang GC, Hsu SL, Tsai JR, Wu WJ, Chen CY, Sheu GT. Extracellular signal-regulated kinase activation and Bcl-2 downregulation mediate apoptosis after gemcitabine treatment partly via a p53-independent pathway. Eur J Pharmacol. 2004;502:169–83.

    Article  CAS  PubMed  Google Scholar 

  31. Santen RJ, Song RX, McPherson R, Kumar R, Adam L, Jeng MH, et al. The role of mitogen-activated protein (MAP) kinase in breast cancer. J Steroid Biochem Mol Biol. 2002;80:239–56.

    Article  CAS  PubMed  Google Scholar 

  32. Nelson JM, Fry DW. Akt, MAPK (Erk1/2), and p38 act in concert to promote apoptosis in response to ErbB receptor family inhibition. J Biol Chem. 2001;276:14842–7.

    Article  CAS  PubMed  Google Scholar 

  33. Persons DL, Yazlovitskaya EM, Cui W, Pelling JC. Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin. Clin Cancer Res. 1999;5:1007–14.

    CAS  PubMed  Google Scholar 

  34. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia. 2003;17:590–603.

    Article  CAS  PubMed  Google Scholar 

  35. Carracedo A, Pandolfi PP. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008;27:5527–41.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Medical Research Center, Catholic University of Korea St. Vincent’s Hospital.

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Surgery, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, 93 Joongboo-Daero Paldal-gu, Suwon, 442-723, Kyounggi-do, Republic of Korea

    Ye Won Jeon & Young Jin Suh

  2. Department of Radiology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea

    Young Ee Ahn & Won Sang Chung

  3. Department of Pathology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea

    Hyun Joo Choi

Authors
  1. Ye Won Jeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young Ee Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Won Sang Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyun Joo Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Young Jin Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Young Jin Suh.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jeon, Y.W., Ahn, Y.E., Chung, W.S. et al. Synergistic effect between celecoxib and luteolin is dependent on estrogen receptor in human breast cancer cells. Tumor Biol. 36, 6349–6359 (2015). https://doi.org/10.1007/s13277-015-3322-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3322-5

Keywords

Search

Navigation