| Popis: |
Background: Lung cancer is by far the leading cause of cancer death worldwide, and 85% of patients are non-small cell lung cancer (NSCLC). NSCLC is still very difficult to treat. Skp2 functions as an oncogene and participates in the processes of NSCLC. Here, we disclose a novel Skp2 inhibitor, which is firstly synthesized by our group based on our previous computer virtual screening and biomolecular interaction analysis (Biacore) technology screening. Methods: To unveil antitumor activity and underlying molecular mechanism of AAA-237, cell proliferation, migration and invasion assays, apoptosis, cell cycle, senescence, and xenograft mouse models were used.Results: AAA-237 inhibited the proliferation of NSCLC cells. AAA-237 regulated the process of epithelial–mesenchymal transition (EMT) by Skp2/Twist axis. Furthermore, AAA-237 induced arresting of cell cycle at G0/G1 phase by regulating the Skp2-Cip/Kip and PI3K/Akt-FOXO1 signaling pathways. More importantly, we found that treatment of high concentration AAA-237 could induce apoptosis of NSCLC cells via the mitochondrial pathway whereas treatment of low concentration AAA-237 for long-term could induce senescence of NSCLC cells by DNA damage. Senolytic drug quercetin could selectively eliminate senescent cells induced by AAA-237. In A549 xenograft nude mice model, AAA-237 dose-dependently inhibited the growth of tumor by inducing apoptosis and senescence.Conclusions: Taken together, we propose that AAA-237 is a promising therapeutic agent of NSCLC, especially when combined with senolytic drug. |
