Cao Fangyuan, Xiao Zhangping, Chen Siwei, Zhao Chunlong, Chen Deng, Haisma Hidde J, Dekker Frank J
Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, the Netherlands.
Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, the Netherlands.
Bioorg Chem. 2021 Dec;117:105396. doi: 10.1016/j.bioorg.2021.105396. Epub 2021 Oct 4.
Non-small-cell lung carcinoma (NSCLC) is one of the most common forms of lung cancer, and a leading cause of cancer death among human beings. There is an urgent demand for novel therapeutics for the treatment of NSCLC to enhance the efficacy of the currently applied Tyrosine kinase inhibitors (TKIs) therapy and to overcome therapy-resistance. Here, we report a novel small-molecule inhibitor that simultaneously targets histone deacetylase (HDAC) and macrophage migration inhibitory factor (MIF). The HDAC/MIF dual inhibitor proved to be toxic for EGFR mutated (H1650, TKI-resistant) or knock out (A549 EGFR) NSCLC cell lines. Further experiments showed that HDAC inhibition inhibits cell survival and proliferation, while MIF inhibition downregulates pAKT or AKT expression level, which both interfere with cell survival. Furthermore, the combination treatment of TKI and HDAC/MIF dual inhibitor showed that the dual inhibitor enhanced TKI inhibitory efficacy, highlighting the advantages of HDAC/MIF dual inhibitor for more effective treatment of NSCLC.
非小细胞肺癌（NSCLC）是肺癌最常见的形式之一，也是人类癌症死亡的主要原因。迫切需要新型疗法来治疗NSCLC，以提高当前应用的酪氨酸激酶抑制剂（TKIs）疗法的疗效并克服治疗耐药性。在此，我们报告一种新型小分子抑制剂，它同时靶向组蛋白去乙酰化酶（HDAC）和巨噬细胞迁移抑制因子（MIF）。HDAC/MIF双重抑制剂被证明对EGFR突变（H1650，TKI耐药）或敲除（A549 EGFR）的NSCLC细胞系有毒性。进一步实验表明，抑制HDAC会抑制细胞存活和增殖，而抑制MIF会下调pAKT或AKT表达水平，这两者都会干扰细胞存活。此外，TKI与HDAC/MIF双重抑制剂的联合治疗表明，双重抑制剂增强了TKI的抑制效果，突出了HDAC/MIF双重抑制剂在更有效治疗NSCLC方面的优势。
