Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 2, pp 249–255 | Cite as

Differential regulation of bladder cancer growth by various glucocorticoids: corticosterone and prednisone inhibit cell invasion without promoting cell proliferation or reducing cisplatin cytotoxicity

  • Hitoshi Ishiguro
  • Takashi Kawahara
  • Yichun Zheng
  • Eiji Kashiwagi
  • Yi Li
  • Hiroshi MiyamotoEmail author
Original Article



A synthetic glucocorticoid, dexamethasone, was recently shown to inhibit bladder cancer cell invasion and metastasis through the glucocorticoid receptor (GR) pathway but increased cell proliferation via inhibiting apoptosis particularly induced by cisplatin. Therefore, comedication with dexamethasone in bladder cancer patients may lead to unfavorable outcomes such as chemoresistance. We here look for any glucocorticoids with inhibitory effects on tumor cell invasion yet inhibitory or at least no stimulatory effects on cell viability.


The effects of 10 glucocorticoids on cell viability were first assessed in three bladder cancer lines. Selected compounds were further assessed for their ability in cell viability and apoptosis, with or without cisplatin, as well as in cell invasion.


Most of the compounds (hydrocortisone, betamethasone, flumethasone, triamcinolone, budesonide, fluticasone propionate, and fludrocortisone acetate) increased GR-positive cell growth, which was similar to or even stronger than the effect of dexamethasone. Nonetheless, two glucocorticoids (corticosterone, prednisone) showed only marginal effects on cell growth of all the lines tested. They did not significantly reduce the effects of cisplatin on cell proliferation or cisplatin-induced apoptosis. Conversely, corticosterone, prednisone, and dexamethasone similarly inhibited cell invasion and expression of related genes, including MMP-9, VEGF, and IL-6, in GR-positive lines.


Corticosterone and prednisone are suggested to have the potential of being harmless, in contrast to dexamethasone, without promoting cell proliferation or inhibiting cytotoxic activity of cisplatin, yet beneficial to bladder cancer patients via suppressing tumor invasion. Our results are thus useful in improving chemotherapy regimens, including optimal glucocorticoids, for urothelial carcinoma.


Bladder cancer Chemotherapy Cisplatin Comedication Glucocorticoids 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Miyamoto H, Miller JS, Fajardo DA, Lee TK, Netto GJ, Epstein JI (2010) Non-invasive papillary urothelial neoplasms: the 2004 WHO/ISUP classification system. Pathol Int 60:1–8PubMedCrossRefGoogle Scholar
  2. 2.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90PubMedCrossRefGoogle Scholar
  3. 3.
    Netto GJ (2012) Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet? Nat Rev Urol 9:41–51CrossRefGoogle Scholar
  4. 4.
    Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E (2010) The human glucocorticoid receptor: molecular basis of biologic function. Steroids 75:1–12PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Basch E, Prestrud AA, Hesketh PJ et al (2011) Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 29:4189–4198PubMedCrossRefGoogle Scholar
  6. 6.
    Schlossmacher G, Stevens A, White A (2011) Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells. J Endocrinol 211:17–25PubMedCrossRefGoogle Scholar
  7. 7.
    Ishiguro H, Kawahara T, Li Y, Miyamoto H (2013) Anti-tumor activities of dexamethasone. In: Sauvage A, Levy M (eds) Dexamethasone: therapeutic uses, mechanism of action and potential side effects. Nova Science Publishers, New York, pp 117–135Google Scholar
  8. 8.
    Zheng Y, Izumi K, Li Y, Ishiguro H, Miyamoto H (2012) Contrary regulation of bladder cancer cell proliferation and invasion by dexamethasone-mediated glucocorticoid receptor signals. Mol Cancer Ther 11:2621–2632PubMedCrossRefGoogle Scholar
  9. 9.
    Ishiguro H, Kawahara T, Zheng Y, Netto GJ, Miyamoto H (2014) Reduced glucocorticoid receptor expression predicts bladder tumor recurrence and progression. Am J Clin Pathol (in press)Google Scholar
  10. 10.
    Zhang C, Mattern J, Haferkamp A et al (2006) Corticosteroid-induced chemotherapy resistance in urological cancers. Cancer Biol Ther 5:59–64PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang C, Wenger T, Mattern J et al (2007) Clinical and mechanistic aspects of glucocorticoid-induced chemotherapy resistance in the majority of solid tumors. Cancer Biol Ther 6:278–287PubMedCrossRefGoogle Scholar
  12. 12.
    Reyes-Moreno C, Frenette G, Boulanger J, Lavergne E, Govindan MV, Koutsilieris M (1995) Mediation of glucocorticoid receptor function by transforming growth factor beta 1 expression in human PC-3 prostate cancer cells. Prostate 26:260–269PubMedCrossRefGoogle Scholar
  13. 13.
    Nishimura K, Nonomura N, Satoh E et al (2001) Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer. J Natl Cancer Inst 93:1739–1746PubMedCrossRefGoogle Scholar
  14. 14.
    Yano A, Fujii Y, Iwai A, Kageyama Y, Kihara K (2006) Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells. Clin Cancer Res 12:3003–3009PubMedCrossRefGoogle Scholar
  15. 15.
    Domingo-Domenech J, Oliva C, Rovira A et al (2006) Interleukin 6, a nuclear factor-κB target, predicts resistance to docetaxel in hormone-independent prostate cancer and nuclear factor-κB inhibition by PS-1145 enhances docetaxel antitumor activity. Clin Cancer Res 12:5578–5586PubMedCrossRefGoogle Scholar
  16. 16.
    Yemelyanov A, Czwornog J, Chebotaev D et al (2007) Tumor suppressor activity of glucocorticoid receptor in the prostate. Oncogene 26:1885–1896PubMedCrossRefGoogle Scholar
  17. 17.
    Gao Q-Z, Lu J–J, Liu Z-D, Zhang H, Wang S-M, Xu H (2008) Dexamethasone suppresses DU145 cell proliferation and cell cycle through inhibition of the extracellular signal-related kinase 1/2 pathway and cyclin D1 expression. Asian J Androl 10:635–641PubMedCrossRefGoogle Scholar
  18. 18.
    Wilson C, Scullin P, Worthington J et al (2008) Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer. Br J Cancer 99:2054–2064PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Meikle AW, Tyler FH (1977) Potency and duration of action of glucocorticoids. Effects of hydrocortisone, prednisone and dexamethasone on human pituitary-adrenal function. Am J Med 63:200–207PubMedCrossRefGoogle Scholar
  20. 20.
    Leung DYM, Hanifin JM, Charlesworth EN et al (1997) Disease management of atopic dermatitis: a practice parameter. Ann Allergy Asthma Immunol 79:197–211PubMedCrossRefGoogle Scholar
  21. 21.
    Singer M, Webb AR (2005) Oxford handbook of critical care, 2nd edn. Oxford University Press, New YorkGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Hitoshi Ishiguro
    • 1
    • 2
  • Takashi Kawahara
    • 1
    • 2
  • Yichun Zheng
    • 1
    • 2
    • 3
  • Eiji Kashiwagi
    • 1
  • Yi Li
    • 2
    • 3
  • Hiroshi Miyamoto
    • 1
    • 2
    • 4
    Email author
  1. 1.Departments of Pathology and UrologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of Rochester Medical CenterRochesterUSA
  3. 3.Department of Urology, 2nd Affiliated HospitalZhejiang University School of MedicineHangzhouChina
  4. 4.The James Buchanan Brady Urological InstituteThe Johns Hopkins HospitalBaltimoreUSA

Personalised recommendations