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:

Basic Research

Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro

Abstract

Background:

The influence of the bisphosphonate zoledronic acid (ZA) on prostate cancer (PC) growth, adhesion and invasive behavior was investigated.

Methods:

PC-3, DU-145 and LNCaP cells were treated with ZA, and tumor-cell growth was then investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, tumor-cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins, as well as migratory properties of the cells, was evaluated. Integrin β subtypes, integrin-dependent signaling, as well as cell-cycle regulating proteins, were analyzed by western blots.

Results:

ZA dose-dependently reduced tumor-cell growth but did not impair tumor–endothelium and tumor–matrix interaction. However, ZA significantly inhibited tumor migration and invasive activity. Cyclin E was reduced by ZA in LNCaP and DU-145, and p21 was elevated in LNCaP cells. p27 was upregulated in all tumor cell lines, compared with the controls. ZA elevated β1-integrin in PC-3 and diminished β4-integrin in PC-3 and DU-145 cells.

Conclusions:

ZA inhibits PC growth and motility but does not influence the mechanical contact between tumor cells and the vascular wall.

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

Similar content being viewed by others

References

  1. Bubendorf L, Schöpfer A, Wagner U, Sauter G, Moch H, Willi N et al. Metastatic patterns of prostate cancer: an autopsy study of 1589 patients. Hum Pathol 2000; 31: 578–583.

    Article  CAS  Google Scholar 

  2. Ho JW . Bisphosphonate stimulation of osteoblasts and osteoblastic metastasis as a mechanism of hypocalcaemia. Med Hypotheses 2012; 78: 377–379.

    Article  CAS  Google Scholar 

  3. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94: 1458–1468.

    Article  CAS  Google Scholar 

  4. Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ . Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 1998; 13: 581–589.

    Article  CAS  Google Scholar 

  5. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004; 96: 879–882.

    Article  CAS  Google Scholar 

  6. Hung TT, Chan J, Russell PJ, Power CA . Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model. PLoS One 2011; 6: e19389.

    Article  CAS  Google Scholar 

  7. Di Salvatore M, Orlandi A, Bagalà C, Quirino M, Cassano A, Astone A et al. Anti-tumour and anti-angiogenetic effects of zoledronic acid on human non-small-cell lung cancer cell line. Cell Prolif 2011; 44: 139–146.

    Article  CAS  Google Scholar 

  8. Koto K, Murata H, Kimura S, Horie N, Matsui T, Nishigaki Y et al. Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis, and shows combined effects with other anticancer agents. Oncol Rep 2010; 24: 233–239.

    CAS  PubMed  Google Scholar 

  9. Sewing L, Steinberg F, Schmidt H, Göke R . The bisphosphonate zoledronic acid inhibits the growth of HCT-116 colon carcinoma cells and induces tumor cell apoptosis. Apoptosis 2008; 13: 782–789.

    Article  CAS  Google Scholar 

  10. Li YY, Chang JW, Chou WC, Liaw CC, Wang HM, Huang JS et al. Zoledronic acid is unable to induce apoptosis, but slows tumor growth and prolongs survival for non-small-cell lung cancers. Lung Cancer 2008; 59: 180–191.

    Article  Google Scholar 

  11. Lee MV, Fong EM, Singer FR, Guenette RS . Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res 2001; 61: 2602–2608.

    CAS  PubMed  Google Scholar 

  12. Oades GM, Senaratne SG, Clarke IA, Kirby RS, Colston KW . Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells. J Urol 2003; 170: 246–252.

    Article  CAS  Google Scholar 

  13. Dumon JC, Journé F, Kheddoumi N, Lagneaux L, Body JJ . Cytostatic and apoptotic effects of bisphosphonates on prostate cancer cells. Eur Urol 2004; 45: 521–528.

    Article  CAS  Google Scholar 

  14. Clyburn RD, Reid P, Evans CA, Lefley DV, Holen I . Increased anti-tumour effects of doxorubicin and ZA in prostate cancer cells in vitro: supporting the benefits of combination therapy. Cancer Chemother Pharmacol 2010; 65: 969–978.

    Article  CAS  Google Scholar 

  15. Almubarak H, Jones A, Chaisuparat R, Zhang M, Meiller TF, Scheper MA . ZA directly suppresses cell proliferation and induces apoptosis in highly tumorigenic prostate and breast cancers. J Carcinog 2011; 10: 2.

    Article  Google Scholar 

  16. Karabulut B, Karaca B, Atmaca H, Kisim A, Uzunoglu S, Sezgin C et al. Regulation of apoptosis-related molecules by synergistic combination of all-trans retinoic acid and ZA in hormone-refractory prostate cancer cell lines. Mol Biol Rep 2011; 38: 249–259.

    Article  CAS  Google Scholar 

  17. Sonnemann J, Bumbul B, Beck JF . Synergistic activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid and the bisphosphonate ZA against prostate cancer cells in vitro. Mol Cancer Ther 2007; 6: 2976–2984.

    Article  CAS  Google Scholar 

  18. Lin P, Sun X, Feng T, Zou H, Jiang Y, Liu Z et al. ADAM17 regulates prostate cancer cell proliferation through mediating cell cycle progression by EGFR/PI3K/AKT pathway. Mol Cell Biochem 2012; 359: 235–243.

    Article  CAS  Google Scholar 

  19. Kannaiyan R, Manu KA, Chen L, Li F, Rajendran P, Subramaniam A et al. Celastrol inhibits tumor cell proliferation and promotes apoptosis through the activation of c-Jun N-terminal kinase and suppression of PI3K/Akt signaling pathways. Apoptosis 2011; 16: 1028–1041.

    Article  CAS  Google Scholar 

  20. Marra M, Santini D, Meo G, Vincenzi B, Zappavigna S, Baldi A et al. Cyr61 downmodulation potentiates the anticancer effects of zoledronic acid in androgen-independent prostate cancer cells. Int J Cancer 2009; 125: 2004–2013.

    Article  CAS  Google Scholar 

  21. Pandhare-Dash J, Mantri CK, Gong Y, Chen Z, Dash C . XMRV accelerates cellular proliferation, transformational activity, and invasiveness of prostate cancer cells by downregulating p27(Kip1). Prostate 2011; e-pub ahead of print 19 September 2011; doi: 10.1002/pros.21491.

  22. Roy S, Singh RP, Agarwal C, Siriwardana S, Sclafani R, Agarwal R . Downregulation of both p21/Cip1 and p27/Kip1 produces a more aggressive prostate cancer phenotype. Cell Cycle 2008; 7: 1828–1835.

    Article  CAS  Google Scholar 

  23. Ananthanarayanan V, Deaton RJ, Amatya A, Macias V, Luther E, Kajdacsy-Balla A et al. Subcellular localization of p27 and prostate cancer recurrence: automated digital microscopy analysis of tissue microarrays. Hum Pathol 2011; 42: 873–881.

    Article  CAS  Google Scholar 

  24. Romics I, Bánfi G, Székely E, Krenács T, Szende B . Expression of p21(waf1/cip1), p27 (kip1), p63 and androgen receptor in low and high Gleason score prostate cancer. Pathol Oncol Res 2008; 14: 307–311.

    Article  Google Scholar 

  25. Fang Z, Zhang T, Dizeyi N, Chen S, Wang H, Swanson KD et al. Androgen receptor enhances p27 degradation in prostate cancer cells through rapid and Selective TORC2 activation. J Biol Chem 2012; 287: 2090–2098.

    Article  CAS  Google Scholar 

  26. Moriceau G, Ory B, Mitrofan L, Riganti C, Blanchard F, Brion R et al. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process. Cancer Res 2010; 70: 10329–10339.

    Article  CAS  Google Scholar 

  27. Morgan TM, Pitts TE, Gross TS, Poliachik SL, Vessella RL, Corey E . RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid. Prostate 2008; 68: 861–871.

    Article  CAS  Google Scholar 

  28. Zaman MH, Trapani LM, Sieminski AL, Mackellar D, Gong H, Kamm RD et al. Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis. Proc Natl Acad Sci USA 2006; 103: 10889–10894.

    Article  CAS  Google Scholar 

  29. Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 2000; 60: 2949–2954.

    CAS  PubMed  Google Scholar 

  30. Montague R, Hart CA, George NJ, Ramani VA, Brown MD, Clarke NW . Differential inhibition of invasion and proliferation by bisphosphonates: anti-metastatic potential of Zoledronic acid in prostate cancer. Eur Urol 2004; 46: 389–401.

    Article  CAS  Google Scholar 

  31. Goel HL, Moro L, King M, Teider N, Centrella M, McCarthy TL et al. Beta1 integrins modulate cell adhesion by regulating insulin-like growth factor-II levels in the microenvironment. Cancer Res 2006; 66: 331–342.

    Article  CAS  Google Scholar 

  32. Ramirez NE, Zhang Z, Madamanchi A, Boyd KL, O’Rear LD, Nashabi A et al. The α2β1 integrin is a metastasis suppressor in mouse models and human cancer. J Clin Invest 2011; 121: 226–237.

    Article  CAS  Google Scholar 

  33. Bonaccorsi L, Carloni V, Muratori M, Salvadori A, Giannini A, Carini M et al. Androgen receptor expression in prostate carcinoma cells suppresses alpha6beta4 integrin-mediated invasive phenotype. Endocrinology 2000; 141: 3172–3182.

    Article  CAS  Google Scholar 

  34. Drake JM, Barnes JM, Madsen JM, Domann FE, Stipp CS, Henry MD . ZEB1 coordinately regulates laminin-332 and {beta}4 integrin expression altering the invasive phenotype of prostate. J Biol Chem 2010; 285: 33940–33948.

    Article  CAS  Google Scholar 

  35. Kovacevic Z, Sivagurunathan S, Mangs H, Chikhani S, Zhang D, Richardson DR . The metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), upregulates p21 via p53-independent mechanisms. Carcinogenesis 2011; 32: 732–740.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Karen Nelson for critically reading the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R A Blaheta.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mani, J., Vallo, S., Barth, K. et al. Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro. Prostate Cancer Prostatic Dis 15, 250–255 (2012). https://doi.org/10.1038/pcan.2012.9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/pcan.2012.9

Keywords

This article is cited by

Search

Quick links