Most advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alectinib and lorlatinib are shown to be effective against NSCLC brain metastasis, while their underlying mechanism of action is unclear. Epithelial-mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs) play important roles in brain metastasis by regulating the blood-brain barrier (BBB). To reveal the molecular function of alectinib and lorlatinib, we explored their effects on the cellular levels of EMT markers: VIM and FN1 and the matrix metalloproteinases MMP-9 and MMP-7. The mRNA and protein levels of VIM, FN1, MMP-9, and MMP-7 were elevated in H3122 cells. However, upon alectinib and lorlatinib treatment the levels were significantly reduced. Similar results were obtained when these experiments were performed either in a dose dependent or time dependent manner. Furthermore, alectinib and lorlatinib also inhibited the cell viability and migration of H3122 cells. Interestingly, in comparison to individual drugs, the combination of alectinib and lorlatinib was found to be substantially more effective. Overall, these results suggest that alectinib and lorlatinib possibly function via the downregulation of MMPs and EMT in NSCLC metastasis.

中文翻译：

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艾乐替尼和劳拉替尼通过调节非小细胞肺癌转移中的 EMT 相关蛋白和 MMP 发挥作用。

大多数晚期非小细胞肺癌 (NSCLC) 患者伴有脑转移，这是死亡率增加的主要原因。间变性淋巴瘤激酶（ALK）基因的融合重排是肺癌脑转移的重要特征。新的 ALK 抑制剂艾乐替尼和劳拉替尼被证明对 NSCLC 脑转移有效，但其潜在作用机制尚不清楚。上皮间质转化 (EMT) 蛋白和基质金属蛋白酶 (MMP) 通过调节血脑屏障 (BBB) 在脑转移中发挥重要作用。为了揭示艾乐替尼和劳拉替尼的分子功能，我们探讨了它们对 EMT 标志物：VIM 和 FN1 以及基质金属蛋白酶 MMP-9 和 MMP-7 的细胞水平的影响。VIM、FN1、MMP-9、H3122 细胞中 MMP-7 升高。然而，在艾乐替尼和劳拉替尼治疗后，水平显着降低。当以剂量依赖或时间依赖的方式进行这些实验时，获得了类似的结果。此外，艾乐替尼和劳拉替尼还抑制了 H3122 细胞的细胞活力和迁移。有趣的是，与单个药物相比，艾乐替尼和劳拉替尼的组合被发现更有效。总体而言，这些结果表明艾乐替尼和劳拉替尼可能通过下调 MMP 和 EMT 在 NSCLC 转移中发挥作用。此外，艾乐替尼和劳拉替尼还抑制了 H3122 细胞的细胞活力和迁移。有趣的是，与单个药物相比，艾乐替尼和劳拉替尼的组合被发现更有效。总体而言，这些结果表明艾乐替尼和劳拉替尼可能通过下调 MMP 和 EMT 在 NSCLC 转移中发挥作用。此外，艾乐替尼和劳拉替尼还抑制了 H3122 细胞的细胞活力和迁移。有趣的是，与单个药物相比，艾乐替尼和劳拉替尼的组合被发现更有效。总体而言，这些结果表明艾乐替尼和劳拉替尼可能通过下调 MMP 和 EMT 在 NSCLC 转移中发挥作用。