Treatment of experimental human breast cancer and lung cancer brain metastases in mice by macitentan, a dual antagonist of endothelin receptors, combined with paclitaxel
Treatment of experimental human breast cancer and lung cancer brain metastases in mice by macitentan, a dual antagonist of endothelin receptors, combined with paclitaxel
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DOI：
10.1093/neuonc/now037
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发表时间：
2016-04-01
期刊：
影响因子：
15.9
通讯作者：
Fidler, Isaiah J.
中科院分区：
文献类型：
--
作者：
Lee, Ho Jeong;Hanibuchi, Masaki;Fidler, Isaiah J.
背景我们最近证明，脑内皮细胞和星形胶质细胞通过内皮素依赖性信号机制保护癌细胞免受化疗。在此，我们评价了马昔腾坦（一种双重内皮素受体（ETAR和ETBR）拮抗剂）治疗实验性乳腺癌和肺癌脑肿瘤的疗效。在细胞毒性试验中测定了马昔腾坦对星形胶质细胞和脑内皮细胞介导的化学保护特性的影响。我们比较了接受溶媒、马昔腾坦、紫杉醇或马昔腾坦+紫杉醇治疗的已确诊MDA-MB-231乳腺癌或PC-14非小细胞肺癌（NSCLC）脑转移瘤小鼠的生存期。通过免疫荧光显微镜观察细胞分裂、凋亡、肿瘤血管和生存相关蛋白的表达。在两种转移模型中，溶媒和紫杉醇给药组的癌细胞和肿瘤相关内皮细胞表达活化形式的AKT和MAPK，但这些蛋白质在接受马昔腾坦的小鼠转移瘤中下调。马昔腾坦抑制了定位于溶媒和紫杉醇处理肿瘤中癌细胞和肿瘤相关内皮细胞的生存相关蛋白Bcl 2L 1、Gsta 5和Twist 1。马昔腾坦或紫杉醇单独给药对生存期无影响。然而，当马昔腾坦与紫杉醇联合使用时，我们注意到癌细胞分裂显著减少，癌细胞和肿瘤相关内皮细胞均发生显著凋亡。此外，马昔腾坦联合紫杉醇治疗通过在35/35只携带脑肿瘤的小鼠中产生完全缓解，显著延长了总生存期。ETAR和ETBR信号的双重拮抗作用使实验性脑转移瘤对紫杉醇敏感，并可能代表脑转移瘤患者的新治疗选择。
Background. We recently demonstrated that brain endothelial cells and astrocytes protect cancer cells from chemotherapy through an endothelin-dependent signaling mechanism. Here, we evaluated the efficacy of macitentan, a dual endothelin receptor (ETAR and ETBR) antagonist, in the treatment of experimental breast and lung cancer brain metastases.Methods. The effect of macitentan on astrocyte- and brain endothelial cell-mediated chemoprotective properties was measured in cytotoxic assays. We compared survival of mice bearing established MDA-MB-231 breast cancer or PC-14 non-small cell lung cancer (NSCLC) brain metastases that were treated with vehicle, macitentan, paclitaxel, or macitentan plus paclitaxel. Cell division, apoptosis, tumor vasculature, and expression of survival-related proteins were assessed by immunofluorescent microscopy.Results. Cancer cells and tumor-associated endothelial cells expressed activated forms of AKTand MAPK in vehicle-and paclitaxeltreated groups in both metastasis models, but these proteins were downregulated in metastases of mice that received macitentan. The survival-related proteins Bcl2L1, Gsta5, and Twist1 that localized to cancer cells and tumor-associated endothelial cells in vehicle-and paclitaxel-treated tumors were suppressed by macitentan. Macitentan or paclitaxel alone had no effect on survival. However, when macitentan was combined with paclitaxel, we noted a significant reduction in cancer cell division and marked apoptosis of both cancer cells and tumor-associated endothelial cells. Moreover, macitentan plus paclitaxel therapy significantly increased overall survival by producing complete responses in 35 of 35 mice harboring brain metastases.Conclusions. Dual antagonism of ETAR and ETBR signaling sensitizes experimental brain metastases to paclitaxel and may represent a new therapeutic option for patients with brain metastases.