nach oben

Cancer Chemotherapy and Pharmacology

Erschienen in:

01.06.2008 | Original Article

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

verfasst von: Tadahiko Kubo, Shoji Shimose, Toshihiro Matsuo, Akira Sakai, Mitsuo Ochi

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2008

Einloggen, um Zugang zu erhalten

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.

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 20:776–790PubMedCrossRef

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 40:276–287PubMedCrossRef

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

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

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 24:1138–1144PubMedCrossRef

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

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 5:2605–2612PubMed

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 18:739–745PubMedCrossRef

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 43:3417–3421PubMed

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 276:40968–40976PubMedCrossRef

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 15:719–727PubMedCrossRef

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 60:2949–2954PubMed

13.

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

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 276:18185–18192PubMedCrossRef

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 20:4543–4552PubMedCrossRef

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 278:724–728PubMedCrossRef

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 14:29–36PubMedCrossRef

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 81:231–241PubMedCrossRef

19.

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

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 47:31–39PubMedCrossRef

21.

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

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 42:1228–1236PubMedCrossRef

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 88:2095–2105PubMedCrossRef

Titel: Efficacy of a nitrogen-containing bisphosphonate, minodronate, in conjunction with a p38 mitogen activated protein kinase inhibitor or doxorubicin against malignant bone tumor cells
verfasst von: Tadahiko Kubo
Shoji Shimose
Toshihiro Matsuo
Akira Sakai
Mitsuo Ochi
Publikationsdatum: 01.06.2008
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2008
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-007-0580-y

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

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

Abstract

Purpose

Methods

Results

Conclusions

Neu im Fachgebiet Onkologie

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

15% bedauern gewählte Blasenkrebs-Therapie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Update Onkologie

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2008

Preclinical studies of treosulfan demonstrate potent activity in Ewing’s sarcoma

Rapid complete remission in multiple myeloma with bortezomib/thalidomide/dexamethasone combination therapy following development of tumor lysis syndrome

In vitro evaluation of the effects of gefitinib on the modulation of cytotoxic activity of selected anticancer agents in a panel of human ovarian cancer cell lines

A phase II study of capecitabine and cisplatin (XP) as first-line chemotherapy in patients with advanced esophageal squamous cell carcinoma

Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia

Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment

Neu im Fachgebiet Onkologie

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

15% bedauern gewählte Blasenkrebs-Therapie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Update Onkologie