Licoisoflavone A inhibits colorectal cancer cell proliferation through targeting CDK2-Cyclin E1 axis-mediated cell cycle transition.

As the second most malignant neoplasm in the world, colorectal cancer (CRC) still needs the novel treatment strategy urgently. Cyclin-dependent kinase 2 (CDK2) has been identified as a potential therapeutic target in CRC research, but the development of CDK2 inhibitors still faces significant challenges. This study was to investigate the efficacy and underlying mechanisms of licoisoflavone A (LA) in targeting CDK2. HCT116 and SW480 human CRC cells were used to evaluate the in vitro anti-CRC activity and CDK2 regulation effect of LA by flow cytometry and Western blot analysis. Molecular docking and CDK2 knockdown cell models were used to investigate the direction interaction between LA and CDK2. Patient-derived CRC organoids and tumor-bearing mice were used to verify the anti-CRC activity and mechanism of LA. As a result, LA significantly inhibited cell proliferation and induced G1/S phase arrest in HCT116 and SW480 cells. LA had direct interaction with CDK2, and not only inhibited the formation of the CDK2/cyclin E1 complex, but also suppressed its kinase activity through the upregulation of p27, thereby inhibiting Rb phosphorylation and arresting the cell cycle in the G1 phase. Moreover, LA exerted anti-CRC effect in CRC organoids and the subcutaneous xenograft tumor mode without evident toxic effects. LA inhibits CRC cell proliferation through targeting the CDK2-Cyclin E1 axis-mediated cell cycle transition. Our research provides compelling evidence that LA may serve as a potential agent for the treatment of CRC, and also provides a rationale to design novel CDK2 inhibitors.