Skip to main content

Advertisement

SpringerLink
Log in

Efficacy of a nitrogen-containing bisphosphonate, minodronate, in conjunction with a p38 mitogen activated protein kinase inhibitor or doxorubicin against malignant bone tumor cells

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

We recently reported the sarcoma-selective antitumor effects of a newly developed nitrogen-containing bisphosphonate, minodronate (MIN), on malignant bone tumors. The aim of this study was to develop efficient combination MIN therapy in malignant bone tumors.

Methods

We examined downstream molecular events of MIN in osteosarcoma and Ewing’s sarcoma cells to search for a partner to combine with MIN. Furthermore, we evaluated the combined effects of MIN and clinically available Doxorubicin (DOX).

Results

We found that MIN inhibited Rap 1A prenylation, and extracellular signal-regulated kinase (ERK) or Akt phosphorylation in osteosarcoma (Saos-2) and Ewing’s sarcoma (SK-ES-1) cells. Interestingly, MIN activated p38 mitogen activated protein kinase (MAPK) only in SK-ES-1 cells and a p38 MAPK inhibitor augmented MIN-induced growth inhibition in SK-ES-1 cells. Doxorubicin (DOX) exerted synergistic effects on Saos-2 and SK-ES-1 cell lines. Daily injection of MIN enhanced the growth inhibition of SK-ES-1 xenograft sarcoma treated by DOX in nude mice.

Conclusions

These findings suggest that the inhibition of the p38 MAPK pathway may be attractive in overcoming cellular resistance against MIN. In the light of clinical settings, MIN may have a beneficial adjuvant role in the DOX treatment.

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
Fig. 5

Similar content being viewed by others

Abbreviations

MIN:

Minodronate

ERK:

Extracellular signal-regulated kinase

MAPK:

Mitogen activated protein kinase

DOX:

Doxorubicin

FBS:

Fetal bovine serum

PBS:

Phosphate buffered saline

References

  1. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jurgens H, Winkler K (2002) Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20:776–790

    Article  PubMed  Google Scholar 

  2. Rodriguez-Galindo C, Spunt SL, Pappo AS (2003) Treatment of Ewing sarcoma family of tumors: current status and outlook for the future. Med Pediatr Oncol 40:276–287

    Article  PubMed  Google Scholar 

  3. Neville-Webbe HL, Holen I, Coleman RE (2002) The anti-tumour activity of bisphosphonates. Cancer Treat Rev 28:305–319

    Article  PubMed  CAS  Google Scholar 

  4. Green JR (2003) Antitumor effects of bisphosphonates. Cancer 97:840–847

    Article  PubMed  Google Scholar 

  5. Kubo T, Shimose S, Matsuo T, Tanaka K, Yasunaga Y, Sakai A, Ochi M (2006) Inhibitory effects of a new bisphosphonate, minodronate, on proliferation and invasion of a variety of malignant bone tumor cells. J Orthop Res 24:1138–1144

    Article  PubMed  CAS  Google Scholar 

  6. Berenbaum MC (1977) Synergy, additivism and antagonism in immunosuppression. A critical review. Clin Exp Immunol 28:1–18

    PubMed  CAS  Google Scholar 

  7. Mizutani Y, Yoshida O, Miki T, Bonavida S (1999) Synergistic cytotoxicity and apoptosis by Apo-2 ligand and adriamycin against bladder cancer cells. Clin Cancer Res 5:2605–2612

    PubMed  CAS  Google Scholar 

  8. Robert J, Illiadis A, Hoerni B, Cano JP, Durand M, Lagarde C (1982) Pharmacokinetics of adriamycin in patients with breast cancer: correlation between pharmacokinetic parameters and clinical short-term response. Eur J Cancer Clin Oncol 18:739–745

    Article  PubMed  CAS  Google Scholar 

  9. Greene RF, Collins JM, Jenkins JF, Speyer JL, Myers CE (1983) Plasma pharmacokinetics of adriamycin and adriamycinol: implications for the design of in vitro experiments and treatment protocols. Cancer Res 43:3417–3421

    PubMed  CAS  Google Scholar 

  10. Tsukada Y, Miyazawa K, Kitamura N (2001) High intensity ERK signal mediates hepatocyte growth factor-induced proliferation inhibition of the human hepatocellular carcinoma cell line HepG2. J Biol Chem 276:40968–40976

    Article  PubMed  CAS  Google Scholar 

  11. Iguchi T, Miyakawa Y, Yamamoto K, Kizaki M, Ikeda Y (2003) Nitrogen-containing bisphosphonates induce S-phase cell cycle arrest and apoptosis of myeloma cells by activating MAPK pathway and inhibiting mevalonate pathway. Cell Signal 15:719–727

    Article  PubMed  CAS  Google Scholar 

  12. Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M, Delmas P, Delaisse JM, Clezardin P (2000) Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 60:2949–2954

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  14. Heron-Milhavet L, Karas M, Goldsmith CM, Baum BJ, LeRoith D (2001) Insulin-like growth factor-I (IGF-I) receptor activation rescues UV-damaged cells through a p38 signaling pathway. Potential role of the IGF-I receptor in DNA repair. J Biol Chem 276:18185–18192

    Article  PubMed  CAS  Google Scholar 

  15. Wang X, McGowan CH, Zhao M, He L, Downey JS, Fearns C, Wang Y, Huang S, Han J (2000) Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol 20:4543–4552

    Article  PubMed  CAS  Google Scholar 

  16. Pillaire MJ, Nebreda AR, Darbon JM (2000) Cisplatin and UV radiation induce activation of the stress-activated protein kinase p38gamma in human melanoma cells. Biochem Biophys Res Commun 278:724–728

    Article  PubMed  CAS  Google Scholar 

  17. Barancik M, Bohacova V, Kvackajova J, Hudecova S, Krizanova O, Breier A (2001) SB203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance. Eur J Pharm Sci 14:29–36

    Article  PubMed  CAS  Google Scholar 

  18. Merrell M, Suarez-Cuervo C, Harris KW, Vaananen HK, Selander KS (2003) Bisphosphonate induced growth inhibition of breast cancer cells is augmented by p38 inhibition. Breast Cancer Res Treat 81:231–241

    Article  PubMed  CAS  Google Scholar 

  19. Dominguez C, Powers DA, Tamayo N (2005) p38 MAP kinase inhibitors: many are made, but few are chosen. Curr Opin Drug Discov Devel 8:421–430

    PubMed  CAS  Google Scholar 

  20. Matsumoto S, Kimura S, Segawa H, Kuroda J, Yuasa T, Sato K, Nogawa M, Tanaka F, Maekawa T, Wada H (2005) Efficacy of the third-generation bisphosphonate, zoledronic acid alone and combined with anti-cancer agents against small cell lung cancer cell lines. Lung Cancer 47:31–39

    Article  PubMed  Google Scholar 

  21. Ural AU, Avcu F (2005) Bisphosphonates may potentiate radiation effects: a new approach in cancer treatment? Biochem Biophys Res Commun 336:373–374

    Article  PubMed  CAS  Google Scholar 

  22. Chen T, Berenson J, Vescio R, Swift R, Gilchick A, Goodin S, LoRusso P, Ma P, Ravera C, Deckert F, Schran H, Seaman J, Skerjanec A (2002) Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol 42:1228–1236

    Article  PubMed  CAS  Google Scholar 

  23. Sato M, Grasser W, Endo N, Akins R, Simmons H, Thompson DD, Golub E, Rodan GA (1991) Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest 88:2095–2105

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the Grants-in-Aids for Scientific Research (C) 1659149100 from the Ministry of Education, Science, Sports, Culture, and Technology of Japan. No benefits in any form have been received from a commercial party related directly or indirectly to the subject of this article.

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Tadahiko Kubo, Shoji Shimose, Toshihiro Matsuo & Mitsuo Ochi

  2. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Akira Sakai

Authors
  1. Tadahiko Kubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shoji Shimose
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshihiro Matsuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akira Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mitsuo Ochi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tadahiko Kubo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kubo, T., Shimose, S., Matsuo, T. et al. Efficacy of a nitrogen-containing bisphosphonate, minodronate, in conjunction with a p38 mitogen activated protein kinase inhibitor or doxorubicin against malignant bone tumor cells. Cancer Chemother Pharmacol 62, 111–116 (2008). https://doi.org/10.1007/s00280-007-0580-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-007-0580-y

Keywords

Search

Navigation