Ying Zhu1,2, Kun-Bin Ke3, Zhong-Kun Xia4, Hong-Jian Li5, Rong Su6, Chao Dong7, Feng-Mei Zhou4, Lin Wang4, Rong Chen8, Shi-Guo Wu9, Hui Zhao3, Peng Gu3, Kwong-Sak Leung10, Man-Hon Wong10, Gang Lu5, Jian-Ying Zhang4, Bing-Hua Jiang4, Jian-Ge Qiu4, Xi-Nan Shi11,12, Marie Chia-Mi Lin13. 1. Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, Yunnan, China. 2. Department of Cadre Medical Branch, The 3rd Affiliated Hospital of Kunming Medical University, Kunming, 650118, Yunnan, China. 3. Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650000, China. 4. Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, Henan, China. 5. CUHK-SDU Joint Laboratory On Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China. 6. Department of Geriatric Cardiology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650000, China. 7. Department of the Second Medical Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital, Kunming, 650000, China. 8. Department of Physiology, Yunnan University of Chinese Medicine, Kunming, 650504, Yunnan, China. 9. Department of Teaching and Research of Formulas of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, 650000, Yunnan, China. 10. Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong, 999077, China. 11. Department of Pathology, Yunnan University of Chinese Medicine, Kunming, 650504, Yunnan, China. xilancixiang@163.com. 12. Department ofMedicine, Southwest Guizhou Vocational and Technical College for Nationalities, Xingyi, 562400, Guizhou, China. xilancixiang@163.com. 13. Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, Henan, China. mcmlin@163.com.
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.
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 humanHCC 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.
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