School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, China.
Eur J Pharmacol. 2023 Dec 5;960:176114. doi: 10.1016/j.ejphar.2023.176114. Epub 2023 Oct 19.
In patients with non-small cell lung cancer (NSCLC), the standard therapy consists of selective tyrosine kinase inhibitors that target epidermal growth factor receptors (EGFR). Nonetheless, their clinical utility is primarily limited by the development of resistance to drugs. HDAC inhibitors have been shown in studies to reduce the level of EGFR that is expressed and downregulate the EGFR-induced phosphorylation of AKT and ERK. Therefore, dual inhibitors of EGFR and HDAC provide a potential approach as combination treatment synergistically inhibited the growth of NSCLC. Herein, we examined the EGFR inhibition effect of twenty compounds which designed and synthesized by us previously. Among them, compounds 12c and 12d exhibited powerful antiproliferative activity against the NCI-H1975 cell line with IC values of 0.48 ± 0.07 and 0.35 ± 0.02 μM, correspondingly. In cell-free kinase assays, both 12c and 12d demonstrated target-specific EGFR inhibition against wild type (EGFR). Furthermore, the expression of EGFR and phosphorylation of the EGF-induced pathways were significantly suppressed under the treatment of 12c and 12d. Besides, both histones H3 and H4 exhibited increased levels of acetylation following 12c and 12d treatment. The animal experiments shown that 12d could prevent the growth of tumor, inhibited the expression of EGFR and the phosphorylation levels of p70 S6K, AKT and p38 MAPK in vivo, and did not cause organ damage to the mice during the experiment. Overall, the results illustrated that compound 12c and 12d could serve as effective EGFR and HDAC dual inhibitors in NSCLC cells. Our work offers an alternative strategy for NSCLC therapy.
在非小细胞肺癌（NSCLC）患者中，标准治疗包括针对表皮生长因子受体（EGFR）的选择性酪氨酸激酶抑制剂。然而，它们的临床应用主要受到药物耐药性的限制。研究表明，HDAC 抑制剂可降低 EGFR 的表达水平，并下调 EGFR 诱导的 AKT 和 ERK 磷酸化。因此，EGFR 和 HDAC 的双重抑制剂作为联合治疗提供了一种潜在的方法，可协同抑制 NSCLC 的生长。在此，我们研究了我们之前设计和合成的二十种化合物对 EGFR 的抑制作用。其中，化合物 12c 和 12d 对 NCI-H1975 细胞系表现出强大的增殖抑制活性，IC 值分别为 0.48±0.07 和 0.35±0.02 μM。在无细胞激酶测定中，12c 和 12d 均表现出针对野生型（EGFR）的靶特异性 EGFR 抑制作用。此外，在 12c 和 12d 的处理下，EGFR 的表达和 EGF 诱导的通路的磷酸化显著受到抑制。此外，组蛋白 H3 和 H4 在 12c 和 12d 处理后乙酰化水平均升高。动物实验表明，12d 可预防肿瘤生长，抑制体内 EGFR 的表达和 p70 S6K、AKT 和 p38 MAPK 的磷酸化水平，并且在实验过程中对小鼠没有造成器官损伤。总的来说，结果表明，化合物 12c 和 12d 可作为 NSCLC 细胞中有效的 EGFR 和 HDAC 双重抑制剂。我们的工作为 NSCLC 治疗提供了一种替代策略。
