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:

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.

• Authors: Tadahiko Kubo, Shoji Shimose, Toshihiro Matsuo, Akira Sakai, Mitsuo Ochi
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 62 Issue 1 Pg. 111-6 (Jun 2008) ISSN: 0344-5704 [Print] Germany
• PMID: 17874104 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Diphosphonates
• Enzyme Inhibitors
• Imidazoles
• Indicators and Reagents
• YM 529
• Doxorubicin
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• GTP-Binding Proteins

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Blotting, Western
• Bone Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Diphosphonates (pharmacology)
• Doxorubicin (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors)
• GTP-Binding Proteins (metabolism)
• Humans
• Imidazoles (pharmacology)
• Indicators and Reagents
• Mice
• Mice, Nude
• Osteosarcoma (drug therapy, pathology)
• Protein Prenylation (drug effects)
• Sarcoma, Ewing (drug therapy, pathology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)