Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins
Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins
复制标题
DOI：
10.1007/s10549-015-3624-8
复制
发表时间：
2015-12-01
影响因子：
3.8
通讯作者：
Rachner, Tilman D.
中科院分区：
文献类型：
--
作者：
Goebel, Andy;Browne, Andrew J.;Rachner, Tilman D.
Wnt抑制剂Dickkopf-1(DKK-1)通过直接抑制成骨细胞分化和间接激活破骨细胞来促进癌症诱导的溶骨性骨损伤。DKK-1在人乳腺癌细胞中高表达，并可被他汀类和氨基双膦酸类等甲氧戊酸途径的抑制剂抑制。然而，抑制DKK-1需要超生理浓度。我们表明，使用他汀类药物和氨基双膦酸类药物顺序阻断甲伐他汀类药物对DKK-1的抑制作用比单独使用单独用药更显着。因此，唑来膦酸与低浓度的他汀类药物(阿托伐他汀、辛伐他汀和瑞舒伐他汀)联合使用可使人成骨肿瘤细胞系MDA-MB-231、MDA-MET和MDA-bone中DKK-1的表达和分泌减少75%(p<；0.05)。用法呢基焦磷酸或香叶基焦磷酸对异丙烯基化的特异性挽救表明，这些作用是通过抑制香叶基香叶酰化而不是通过抑制法呢化来实现的。此外，低浓度的他汀类药物(1阿托伐他汀或0.25阿托伐他汀或0.25阿托伐他汀)与唑来膦酸在低浓度时联合使用，可使乳腺癌来源的DKK-1介导的C2C12细胞成骨标志物抑制作用至少逆转50%(p<；0.05)。最后，在AS皮下注射阿托伐他汀和唑来膦酸的小鼠模型中，与未治疗的小鼠相比，肿瘤内注射阿托伐他汀和唑来膦酸使人DKK-1的血清水平降低了25%。因此，我们的研究表明，甲氧戊酸途径的顺序阻断允许低浓度的他汀类药物和氨基双膦酸类药物的联合使用。这种组合仍然显著抑制乳腺癌来源的DKK-1，使其不再能抑制Wnt介导的成骨细胞分化。
The Wnt-inhibitor dickkopf-1 (DKK-1) promotes cancer-induced osteolytic bone lesions by direct inhibition of osteoblast differentiation and indirect activation of osteoclasts. DKK-1 is highly expressed in human breast cancer cells and can be suppressed by inhibitors of the mevalonate pathway such as statins and amino-bisphosphonates. However, supraphysiological concentrations are required to suppress DKK-1. We show that a sequential mevalonate pathway blockade using statins and amino-bisphosphonates suppresses DKK-1 more significantly than the individual agents alone. Thus, the reduction of the DKK-1 expression and secretion in the human osteotropic tumor cell lines MDA-MB-231, MDA-MET, and MDA-BONE by zoledronic acid was potentiated by the combination with low concentrations of statins (atorvastatin, simvastatin, and rosuvastatin) by up to 75 % (p < 0.05). The specific rescue of prenylation using farnesyl pyrophosphate or geranylgeranyl pyrophosphate revealed that these effects were mediated by suppressed geranylgeranylation rather than by suppressed farnesylation. Moreover, combining low concentrations of statins (1 A mu M atorvastatin or 0.25 A mu M simvastatin) and zoledronic acid at low concentrations resulted in an at least 50 % reversal of breast cancer-derived DKK-1-mediated inhibition of osteogenic markers in C2C12 cells (p < 0.05). Finally, the intratumoral injection of atorvastatin and zoledronic acid in as subcutaneous MDA-MB-231 mouse model reduced the serum level of human DKK-1 by 25 % compared to untreated mice. Hence our study reveals that a sequential mevalonate pathway blockade allows for the combined use of low concentration of statins and amino-bisphosphonates. This combination still significantly suppresses breast cancer-derived DKK-1 to levels where it can no longer inhibit Wnt-mediated osteoblast differentiation.