Kubista B, Trieb K, Sevelda F, Toma C, Arrich F, Heffeter P, Elbling L, Sutterlüty H, Scotlandi K, Kotz R, Micksche M, Berger W
Department of Orthopaedics, Vienna General Hospital and Medical University of Vienna, Vienna, Austria.
J Orthop Res. 2006 Jun;24(6):1145-52. doi: 10.1002/jor.20129.
Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N = 9). Exposure to ZOL at low micromolar concentrations induced a dose- and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy.
基于新辅助化疗，骨肉瘤患者的预后有了显著改善。然而，由于部分患者亚组存在治疗耐药性，开发新的治疗策略仍然至关重要。我们研究的目的是测试含氮双膦酸盐唑来膦酸（ZOL）对骨肉瘤细胞系（N = 9）的作用。在低微摩尔浓度下暴露于ZOL会诱导DNA合成和细胞周期进程呈剂量和时间依赖性阻滞，随后出现微丝崩解和凋亡诱导。ZOL诱导的细胞周期在S期积累伴随着细胞周期蛋白和细胞周期蛋白依赖性激酶抑制剂表达的显著变化，其中细胞周期蛋白E和D1明显缺失。ZOL不仅抑制骨肉瘤细胞的生长，还抑制其迁移。甲羟戊酸途径中间体香叶基香叶醇（GGOH）而非法尼基醇（FOH）显著抑制ZOL对骨肉瘤细胞的抗癌作用。相应地，ZOL敏感性与未异戊二烯化的Rap1所表明的蛋白质香叶基香叶酰化阻滞相关。即使是高水平的P-糖蛋白过表达（这在耐药骨肉瘤中经常出现）也不会损害ZOL的抗癌活性。总之，我们的数据表明，选择性在骨中积累的ZOL是一种有望改善骨肉瘤治疗的药物。
