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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