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

Molecular Medicine

Marie Chia-mi Lin¹  Zhong-Kun Xia¹  Bing-Hua Jiang¹  Jian-Ge Qiu¹  Lin Wang¹  Feng-Mei Zhou¹  Jian-Ying Zhang¹  Ying Zhu²  Gang Lu³  Hong-Jian Li³  Kwong-Sak Leung⁴  Man-Hon Wong⁴  Rong Su⁵  Xi-Nan Shi⁶  Rong Chen⁷  Shi-Guo Wu⁸  Kun-Bin Ke⁹  Peng Gu⁹  Hui Zhao⁹  Chao Dong^1,10 

[1] Academy of Medical Science, Zhengzhou University;Biomedical Engineering Research Center, Kunming Medical University;CUHK-SDU Joint Laboratory On Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong;Department of Computer Science and Engineering, The Chinese University of Hong Kong;Department of Geriatric Cardiology, The 1st Affiliated Hospital of Kunming Medical University;Department of Pathology, Yunnan University of Chinese Medicine;Department of Physiology, Yunnan University of Chinese Medicine;Department of Teaching and Research of Formulas of Chinese Medicine, Yunnan University of Chinese Medicine;Department of Urology, The 1st Affiliated Hospital of Kunming Medical University;Department of the Second Medical Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital;

关键词: Cyclin-dependent kinases 2/4/6;    Hepatocellular carcinoma;    Vanoxerine dihydrochloride;    Triple inhibitor;    Drug combination;   

DOI  :  10.1186/s10020-021-00269-4

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown