Efficacy of a nitrogen-containing bisphosphonate, minodronate, in conjunction with a p38 mitogen activated protein kinase inhibitor or doxorubicin against malignant bone tumor cells.
OBJECTIVE
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.
Kubo
Tadahiko
T
Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. kubot@hiroshima-u.ac.jp
Shimose
Shoji
S
Matsuo
Toshihiro
T
Sakai
Akira
A
Ochi
Mitsuo
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007202:Indicators and Reagents; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology; D017368:Protein Prenylation / Q000187:drug effects; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000903:Antibiotics, Antineoplastic; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007202:Indicators and Reagents; C087958:YM 529; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins