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

Molecular Medicine

Lin Wang¹  Jian-Ge Qiu¹  Feng-Mei Zhou¹  Marie Chia-mi Lin¹  Jian-Ying Zhang¹  Zhong-Kun Xia¹  Bing-Hua Jiang¹  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  Hui Zhao⁹  Peng Gu⁹  Chao Dong^1,10 

[1] Academy of Medical Science, Zhengzhou University, 450000, Zhengzhou, Henan, China;Biomedical Engineering Research Center, Kunming Medical University, 650500, Kunming, Yunnan, China;Department of Cadre Medical Branch, The 3rd Affiliated Hospital of Kunming Medical University, 650118, Kunming, Yunnan, China;CUHK-SDU Joint Laboratory On Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China;Department of Computer Science and Engineering, The Chinese University of Hong Kong, 999077, Hong Kong, China;Department of Geriatric Cardiology, The 1st Affiliated Hospital of Kunming Medical University, 650000, Kunming, China;Department of Pathology, Yunnan University of Chinese Medicine, 650504, Kunming, Yunnan, China;Department ofMedicine, Southwest Guizhou Vocational and Technical College for Nationalities, 562400, Xingyi, Guizhou, China;Department of Physiology, Yunnan University of Chinese Medicine, 650504, Kunming, Yunnan, China;Department of Teaching and Research of Formulas of Chinese Medicine, Yunnan University of Chinese Medicine, 650000, Kunming, Yunnan, China;Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, 650000, Kunming, China;Department of the Second Medical Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital, 650000, Kunming, China;

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: Springer

【 摘 要 】

BackgroundCyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC).MethodsWe 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.ResultsWe 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.ConclusionsThe 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】

CC BY