首页> 外文期刊>Bone >Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase.
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Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase.

机译:含氮的双膦酸盐可以抑制体内血管生成,而无需法呢基焦磷酸合酶的参与。

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Nitrogen-containing bisphosphonates (N-BPs) are widely used to block bone destruction associated with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. More specifically, once internalized by osteoclasts, N-BPs block the activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. In addition to their antiresorptive activity, preclinical evidence shows that N-BPs have antiangiogenic properties. However, the exact reasons for which N-BPs inhibit angiogenesis remain largely unknown. Using different angiogenesis models, we examined here the effects of zoledronate, risedronate and three structural analogs of risedronate (NE-58025, NE-58051 and NE-10790) with lower potencies to inhibit FPPS activity. Risedronate and zoledronate were much more potent than NE-compounds at inhibiting both endothelial cell proliferation in vitro and vessel sprouting in the chicken egg chorioallantoic membrane (CAM) assay. In addition, only risedronate and zoledronate inhibited the revascularization of the prostate gland in testosterone-stimulated castrated rats. Moreover, as opposed to NE-compounds, risedronate and zoledronate induced intracellular accumulation of isopentenyl pyrophosphate (IPP) in endothelial cells by blocking the activity of the IPP-consuming enzyme FPPS. Thus, these results indicated that N-BPs inhibited angiogenesis in a FPPS-dependent manner. However, drug concentrations used to inhibit angiogenesis, both in vitro and in the CAM and prostate gland assays, were high. In contrast, a low concentration of risedronate (1 muM) was sufficient to inhibit blood vessel formation in the ex vivo rat aortic ring assay. Moreover, NE-58025 (which had a 7-fold lower potency than risedronate to inhibit FPPS activity) was as effective as risedronate to reduce angiogenesis in the rat aortic ring assay. In conclusion, our results suggest that low concentrations of N-BPs inhibit angiogenesis in a FPPS-independent manner, whereas higher drug concentrations were required to inhibit FPPS activity in vivo.
机译:含氮双膦酸盐(N-BPs)被广泛用于阻止与骨转移相关的骨破坏,因为它们是破骨细胞介导的骨吸收的有效抑制剂。更具体地说,一旦被破骨细胞内化,N-BP会阻断法呢基焦磷酸合酶(FPPS)(甲羟戊酸途径中的关键酶)的活性。除了其抗吸收活性外,临床前证据还表明N-BP具有抗血管生成特性。然而,N-BPs抑制血管生成的确切原因仍然未知。使用不同的血管生成模型,我们在这里检查了唑来膦酸盐,利塞膦酸盐和利塞膦酸盐的三种结构类似物(NE-58025,NE-58051和NE-10790)的作用,它们具有较低的抑制FPPS活性的能力。在鸡卵绒膜尿囊膜(CAM)分析中,利塞膦酸和唑来膦酸在抑制内皮细胞增殖和抑制血管发芽方面比NE化合物有效得多。另外,在睾丸激素刺激的去势大鼠中,仅利塞膦酸盐和唑来膦酸盐抑制前列腺的血运重建。此外,与NE化合物相反,利塞膦酸盐和唑来膦酸盐通过阻断消耗IPP的酶FPPS的活性,在内皮细胞中诱导细胞内异戊烯基焦磷酸酯(IPP)的积累。因此,这些结果表明N-BP以FPPS依赖性方式抑制血管生成。然而,在体外以及在CAM和前列腺测定中,用于抑制血管生成的药物浓度很高。相反,在离体大鼠主动脉环测定中,低浓度的利塞膦酸盐(1μM)足以抑制血管形成。此外,NE-58025(在抑制FPPS活性方面,其功效比利塞膦酸盐低7倍)与利塞膦酸盐在减少大鼠主动脉环测定中的血管生成方面一样有效。总之,我们的结果表明,低浓度的N-BPs以FPPS独立的方式抑制血管生成,而在体内抑制FPPS活性需要更高的药物浓度。

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