Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.11861/7388
Title: Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma
Authors: Zhu, Ying 
Ke, Kun-Bin 
Xia, Zhong-Kun 
Li, Hong-Jian 
Su, Rong 
Dong, Chao 
Zhou, Feng-Mei 
Wang, Lin 
Chen, Rong 
Wu, Shi-guo 
Zhao, Hui 
Gu, Peng 
Prof. LEUNG Kwong Sak 
Wong, Man-Hon 
Lu, gang 
Zhang, Jian-ying 
Jiang, Bing- Hua 
Qiu, Jian-Ge 
Shi, Xi-Nan 
Lin, Marie, Chia-mi 
Issue Date: 2021
Source: Molecular Medicine 27, 2021, vol. 15
Journal: Molecular Medicine 
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 of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC. Results We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxicdrugin human HCC QGY7703 and Huh7 cells (IC50: 3.79 μM for QGY7703and 4.04 μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1-arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40 mg/kg, i.p.) injection for 21 days produced significant anti-tumor activity (p < 0.05), which was comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerinedihydrochloride treatment group. Conclusions The present study isthe first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.
Type: Peer Reviewed Journal Article
URI: http://hdl.handle.net/20.500.11861/7388
ISSN: 1528-3658
DOI: 10.1186/s10020-021-00269-4
Appears in Collections:Applied Data Science - Publication

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