We found a match
Your institution may have rights to this item. Sign in to continue.
- 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; Leung, Kwong-Sak; Wong, Man-Hon; Lu, Gang; Zhang, Jian-Ying; Jiang, Bing-Hua; Qiu, Jian-Ge; Shi, Xi-Nan; Lin, Marie Chia-mi
- 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.
- Subjects
HEPATOCELLULAR carcinoma; CYCLIN-dependent kinases; RETINOBLASTOMA protein; INJECTIONS; CELL cycle; PHOSPHORYLATION
- Publication
Molecular Medicine, 2021, Vol 27, Issue 1, p1
- ISSN
1076-1551
- Publication type
Article
- DOI
10.1186/s10020-021-00269-4