Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process.
Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process.
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DOI：
10.1158/0008-5472.can-10-0578
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Heymann D
中科院分区：
文献类型：
--
作者：
Moriceau G;Ory B;Mitrofan L;Riganti C;Blanchard F;Brion R;Charrier C;Battaglia S;Pilet P;Denis MG;Shultz LD;Mönkkönen J;Rédini F;Heymann D
尽管最近骨肉瘤的治疗管理有所改善，但在改善化疗反应方面仍存在挑战，需要新的策略来提高患者的总体生存率。在这项研究中，我们研究了RAD001 （Everolimus®），一种新的口服mTOR抑制剂，对人和小鼠骨肉瘤细胞生长的影响，无论是单独使用还是与唑来膦酸盐（ZOL）联合使用，唑来膦酸盐是一种用于治疗骨转移的骨质疏松药物。RAD001以剂量和时间依赖的方式抑制骨肉瘤细胞增殖，不改变细胞周期分布。与单独处理相比，ZOL联合使用增强了这种细胞增殖抑制作用，降低了PI3K/mTOR信号传导。值得注意的是，与RAD001相比，ZOL在对两种药物敏感和耐药的骨肉瘤细胞系中下调异戊二烯化膜结合Ras，同时增加非异戊二烯化细胞质Ras。此外，ZOL和RAD001协同降低Ras异戊二烯化和gtp结合的Ras水平。此外，在两种小鼠成骨细胞或溶骨性骨肉瘤模型中，该药物联合使用可减少肿瘤的发展。我们发现ZOL可以逆转RAD001在骨肉瘤中的耐药性，与RAD001联合使用时限制骨肉瘤细胞的生长。我们的发现为进一步研究mTOR和甲羟戊酸途径抑制剂的应用提供了合理的依据，这些抑制剂可以限制蛋白质戊酰化途径。
Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. In this study, we investigated vivo the effects of RAD001 (Everolimus®), a new orally available mTOR inhibitor, on the growth of human and mouse osteosarcoma cells either alone and in combination with zoledronate (ZOL), an osteoporesis drug which is used to treat bone metastases. RAD001 inhibited osteosarcoma cell proliferation in a dose- and time-dependent manner with no modification of cell cycle distribution. Combination with ZOL augmented this inhibition of cell proliferation, decreasing PI3K/mTOR signaling compared to single treatments. Notably, in contrast to RAD001, ZOL downregulated isoprenylated membrane-bound Ras concomitantly to an increase of non-isoprenylated cytosolic Ras in sensitive- and resistant-osteosarcoma cell lines to both drugs. Moreover, ZOL and RAD001 synergized to decrease Ras isoprenylation and GTP-bound Ras levels. Further, the drug combination reduced tumor development in two murine models of osteoblastic or osteolytic osteosarcoma. We found that ZOL could reverse RAD001 resistance in osteosarcoma, limiting osteosarcoma cell growth in combination with RAD001. Our findings rationalize further study of the applications of mTOR and mevalonate pathway inhibitors that can limit protein prenylation pathways.