The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing 100050, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial, People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.
Pharmacol Res. 2022 Jul;181:106259. doi: 10.1016/j.phrs.2022.106259. Epub 2022 May 13.
Lung cancer is by far the leading cause of cancer death worldwide, and 85% of patients are diagnosed with non-small cell lung cancer (NSCLC), which is still very difficult to treat. Skp2 functions as an oncogene that participates in processes of many cancers. Here, we report a novel Skp2 inhibitor AAA-237 that binds to Skp2 protein and inhibits the proliferation of the NSCLC cells. We further investigated the anti-NSCLC mechanism of AAA-237 and found that it arrested the cell cycle at the G0/G1 phase by targeting Skp2 to reduce the degradation of p21Cip1 and p27Kip1 or by transcriptionally activating FOXO1 to increase the mRNA expression of p21Cip1 and p27Kip1. More importantly, we found that treatment of a high concentration AAA-237 could induce apoptosis of NSCLC cells and treatment of a low AAA-237 concentration for a longer time could induce senescence of NSCLC cells. Similar results were found in nude mice xenografted with A549 cells. AAA-237 inhibited tumor growth by inducing apoptosis and senescence in a dose-dependent manner. Considering these results, we propose that AAA-237 could be a promising therapeutic drug for treating patients with NSCLC.
肺癌是目前全球癌症死亡的主要原因，85%的患者被诊断为非小细胞肺癌（NSCLC），这种癌症仍然很难治疗。Skp2 作为一种癌基因，参与了许多癌症的发生过程。在这里，我们报告了一种新型的 Skp2 抑制剂 AAA-237，它与 Skp2 蛋白结合，抑制 NSCLC 细胞的增殖。我们进一步研究了 AAA-237 的抗 NSCLC 机制，发现它通过靶向 Skp2 减少 p21Cip1 和 p27Kip1 的降解，或通过转录激活 FOXO1 增加 p21Cip1 和 p27Kip1 的 mRNA 表达，将细胞周期阻滞在 G0/G1 期。更重要的是，我们发现高浓度的 AAA-237 处理可诱导 NSCLC 细胞凋亡，而低浓度的 AAA-237 处理更长时间可诱导 NSCLC 细胞衰老。在 A549 细胞裸鼠异种移植模型中也发现了类似的结果。AAA-237 通过诱导凋亡和衰老以剂量依赖的方式抑制肿瘤生长。鉴于这些结果，我们提出 AAA-237 可能是治疗 NSCLC 患者的一种有前途的治疗药物。
