Göbel Andy, Thiele Stefanie, Browne Andrew J, Rauner Martina, Zinna Valentina M, Hofbauer Lorenz C, Rachner Tilman D
Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cancer Lett. 2016 May 28;375(1):162-171. doi: 10.1016/j.canlet.2016.03.004. Epub 2016 Mar 8.
Amino-bisphosphonates are antiresorptive drugs for the treatment of osteolytic bone metastases, which are frequently caused by breast and other solid tumors. Like statins, amino-bisphosphonates inhibit the mevalonate pathway. Direct anti-tumor effects of amino-bisphosphonates and statins have been proposed, although high concentrations are required to achieve these effects. Here, we demonstrate that the treatment of different human breast cancer cell lines (MDA-MB-231, MDA-Bone, and MDA-Met) by combined inhibition of the mevalonate pathway using statins and zoledronic acid at the same time significantly reduces the concentrations required to achieve a meaningful anti-tumor effect over a single agent approach (50% reduction of cell vitality and 4-fold increase of apoptosis; p < 0.05). The effects were mediated by suppressed protein geranylation that caused an accumulation of GTP-bound RhoA and CDC42. Importantly, the knockdown of both proteins prior to mevalonate pathway inhibition reduced apoptosis by up to 65% (p < 0.01), indicating the accumulation of the GTP-bound GTPases as the mediator of apoptosis. Our results point to effective anti-tumor effects in breast cancer by the combination of statins and zoledronic acid and warrant further validation in preclinical settings.
氨基双膦酸盐是用于治疗溶骨性骨转移的抗吸收药物，溶骨性骨转移通常由乳腺癌和其他实体瘤引起。与他汀类药物一样，氨基双膦酸盐抑制甲羟戊酸途径。虽然需要高浓度才能实现这些作用，但氨基双膦酸盐和他汀类药物的直接抗肿瘤作用已被提出。在此，我们证明，同时使用他汀类药物和唑来膦酸联合抑制甲羟戊酸途径来处理不同的人乳腺癌细胞系（MDA-MB-231、MDA-Bone和MDA-Met），与单一药物方法相比，可显著降低实现有意义抗肿瘤作用所需的浓度（细胞活力降低50%，凋亡增加4倍；p<0.05）。这些作用是由抑制蛋白质香叶基化介导的，蛋白质香叶基化导致结合GTP的RhoA和CDC42积累。重要的是，在抑制甲羟戊酸途径之前敲低这两种蛋白质可使凋亡减少多达65%（p<0.01），表明结合GTP的GTP酶的积累是凋亡的介质。我们的结果表明他汀类药物和唑来膦酸联合使用对乳腺癌具有有效的抗肿瘤作用，值得在临床前环境中进一步验证。
