Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma

• DOI: 10.1186/s10020-021-00269-4
• Publication Date: 2021-02-12T12:16:44Z
• Authors: Ying Zhu; Kun-Bin Ke; Zhong-Kun Xia; Hong-Jian Li; Rong Su; Chao Dong; Feng-Mei Zhou; Lin Wang; Rong Chen; Shi-Guo Wu; Hui Zhao; Peng Gu; Kwong-Sak Leung; Man-Hon Wong; Gang Lu; Jian-Ying Zhang; Bing-Hua Jiang; Jian-Ge Qiu; Xi-Nan Shi; Marie Chia-mi Lin
• Keywords: IC50; Cyclin E; Cyclin A

Abstract Background Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). Methods We used the combination computational experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for treatment HCC. Results identified vanoxerine dihydrochloride as new inhibitor, strong cytotoxicdrugin human HCC QGY7703 Huh7 cells (IC50: 3.79 μM QGY7703and 4.04 cells). In cells, caused G1-arrest, induced apoptosis, reduced expressions CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), well phosphorylation Rb. Drug study indicated that 5-Fu produced synergistic cytotoxicity vitro cells. Finally, vivo BALB/C nude mice subcutaneously xenografted with (40 mg/kg, i.p.) injection 21 days significant anti-tumor activity (p < 0.05), which was comparable achieved by (10 i.p.), resulted effect. Immunohistochemistry staining tumor tissues also revealed significantly Rb CDK2/4/6in vanoxerinedihydrochloride group. Conclusions The present isthe first report identifying triple inhibitor dihydrochloride, demonstrated this drug represents novel therapeutic strategy treatment.