Efficacy of a nitrogen-containing bisphosphonate, minodronate, in conjunction with a p38 mitogen activated protein kinase inhibitor or doxorubicin against malignant bone tumor cells
Efficacy of a nitrogen-containing bisphosphonate, minodronate, in conjunction with a p38 mitogen activated protein kinase inhibitor or doxorubicin against malignant bone tumor cells
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DOI：
10.1007/s00280-007-0580-y
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发表时间：
2008-06-01
影响因子：
3
通讯作者：
Ochi, Mitsuo
中科院分区：
文献类型：
--
作者：
Kubo, Tadahiko;Shimose, Shoji;Ochi, Mitsuo
目的我们最近报道了一种新开发的含氮双膦酸盐米诺磷酸酯(MIN)对恶性骨肿瘤的选择性抗肿瘤作用。本研究的目的是建立有效的联合MIN治疗恶性骨肿瘤的方法。方法检测骨肉瘤和尤文氏肉瘤细胞中MIN的下游分子事件，寻找与MIN结合的伴侣。结果Min可抑制骨肉瘤(Saos-2)和尤文氏肉瘤(SK-ES-1)细胞中Rap 1A的预苯化，抑制细胞外信号调节激酶(ERK)或Akt的磷酸化。有趣的是，MIN只在SK-ES-1细胞中激活p38丝裂原活化蛋白激酶(MAPK)，而p38 MAPK抑制剂增强了MIN诱导的SK-ES-1细胞的生长抑制。阿霉素(DOX)对Saos-2和SK-ES-1细胞有协同作用。结论抑制p38MAPK通路可能在克服细胞对MIN的耐药性中起重要作用。根据临床情况，MIN可能在DOX治疗中起到有益的辅助作用。
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.