Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
Department of Respiratory & Critical Care Medicine, Karl Landsteiner Institute of Lung Research & Pulmonary Oncology, Vienna, Austria.
Invest New Drugs. 2022 Apr;40(2):215-223. doi: 10.1007/s10637-021-01181-8. Epub 2021 Oct 1.
In the absence of suitable molecular markers, non-small cell lung cancer (NSCLC) patients have to be treated with chemotherapy with poor results at advanced stages. Therefore, the activity of the anticancer marine drug fascaplysin was tested against primary NSCLC cell lines established from pleural effusions. Cytotoxicity of the drug or combinations were determined using MTT assays and changes in intracellular phosphorylation by Western blot arrays. Fascaplysin revealed high cytotoxicity against NSCLC cells and exhibit an activity pattern different of the standard drug cisplatin. Furthermore, fascaplysin synergizes with the EGFR tyrosine kinase inhibitor (TKI) afatinib to yield a twofold increased antitumor effect. Interaction with the Chk1/2 inhibitor AZD7762 confirm the differential effects of fascplysin and cisplatin. Protein phosphorylation assays showed hypophosphorylation of Akt1/2/3 and ERK1/2 as well as hyperphosphorylation of stress response mediators of H1299 NSCLC cells. In conclusion, fascaplysin shows high cytotoxicity against pleural primary NSCLC lines that could be further boosted when combined with the EGFR TKI afatinib.
在缺乏合适的分子标志物的情况下，非小细胞肺癌（NSCLC）患者不得不接受化疗，但在晚期阶段效果不佳。因此，对来自胸腔积液的原发性 NSCLC 细胞系进行了抗癌海洋药物 fascaplysin 的活性测试。使用 MTT 测定法和 Western blot 阵列测定药物或组合的细胞毒性和细胞内磷酸化变化。Fascaplysin 对 NSCLC 细胞表现出高细胞毒性，并表现出与标准药物顺铂不同的活性模式。此外，fascaplysin 与表皮生长因子受体酪氨酸激酶抑制剂（TKI）阿法替尼协同作用，产生两倍的抗肿瘤作用。与 Chk1/2 抑制剂 AZD7762 的相互作用证实了 fascplysin 和顺铂的不同作用。蛋白磷酸化测定显示 Akt1/2/3 和 ERK1/2 的低磷酸化以及 H1299 NSCLC 细胞应激反应介质的高磷酸化。总之，fascaplysin 对胸腔积液原发性 NSCLC 细胞系表现出高细胞毒性，当与表皮生长因子受体 TKI 阿法替尼联合使用时，其效果可进一步增强。
