loading page

Discovery of a new CDK4/6 and PI3K/AKT multiple kinase inhibitor aminoquinol for the treatment of hepatocellular carcinoma
  • +19
  • Zhongkun Xia,
  • Jian-Ge Qiu,
  • Hongjian Li,
  • Rong Chen,
  • Kunbin ke,
  • Chao Dong,
  • Ying Zhu,
  • Shiguo Wu,
  • Rongping Zhang,
  • Zhuoran Meng,
  • Hui Zhao,
  • Peng Gu,
  • Kwong-Sak Leung,
  • Man-Hon Wong,
  • Xiaodong Liu,
  • Fengmei Zhou,
  • Jianying Zhang,
  • Yating Yao,
  • Sijia Wang,
  • Marie Chia-mi Lin,
  • XiNan Shi,
  • Binghua Jiang
Zhongkun Xia
Zhengzhou University
Author Profile
Jian-Ge Qiu
Zhengzhou University
Author Profile
Hongjian Li
SDIVF R&D Centre
Author Profile
Rong Chen
Yunnan University of Traditional Chinese Medicine
Author Profile
Kunbin ke
The 1st Affiliated Hospital of Kunming Medical University
Author Profile
Chao Dong
The 3rd Affiliated Hospital of Kunming Medical University
Author Profile
Ying Zhu
The 3rd Affiliated Hospital of Kunming Medical University
Author Profile
Shiguo Wu
Yunnan University of Traditional Chinese Medicine
Author Profile
Rongping Zhang
Yunnan University of Traditional Chinese Medicine
Author Profile
Zhuoran Meng
Yunnan University of Traditional Chinese Medicine
Author Profile
Hui Zhao
The 1st Affiliated Hospital of Kunming Medical University
Author Profile
Peng Gu
The 1st Affiliated Hospital of Kunming Medical University
Author Profile
Kwong-Sak Leung
The Chinese University of Hong Kong
Author Profile
Man-Hon Wong
The Chinese University of Hong Kong
Author Profile
Xiaodong Liu
Chinese University of Hong Kong
Author Profile
Fengmei Zhou
Zhengzhou University
Author Profile
Jianying Zhang
Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University
Author Profile
Yating Yao
Zhengzhou University
Author Profile
Sijia Wang
Zhengzhou University
Author Profile
Marie Chia-mi Lin
Zhengzhou University
Author Profile
XiNan Shi
Yunnan University of Traditional Chinese Medicine

Corresponding Author:[email protected]

Author Profile
Binghua Jiang
Zhengzhou University
Author Profile

Abstract

Background: Hepatocellular carcinoma (HCC) is a lethal malignancy lacking effective treatment. The Cyclin-dependent kinases 4/6 (CDK4/6) and PI3K/AKT signal pathways play pivotal roles in carcinogenesis and are promising therapeutic targets for HCC. Here we identified a new CDK4/6 and PI3K/AKT multi-kinase inhibitor for the treatment of HCC. Methods: Using a repurposing and ensemble docking methodology, we screened a library of worldwide approved drugs to identify candidate CDK4/6 inhibitors. By MTT, apoptosis, and flow cytometry analysis, we investigated the effects of candidate drug in reducing cell-viability´╝îinducing apoptosis, and causing cell-cycle arrest. The drug combination and thermal proteomic profiling (TPP) method were used to investigate whether the candidate drug produced antagonistic effect. The in vivo anti-cancer effect was performed in BALB/C nude mice subcutaneously xenografted with Huh7 cells. Results: We demonstrated for the first time that the anti-plasmodium drug aminoquinol is a new CDK4/6 and PI3K/AKT inhibitor. Aminoquinol significantly decreased cell viability, induced apoptosis, increased the percentage of cells in G1 phase. Drug combination screening indicated that aminoquinol could produce antagonistic effect with the PI3K inhibitor LY294002. TPP analysis confirmed that aminoquinol significantly stabilized CDK4, CDK6, PI3K and AKT proteins. Finally, in vivo study in Huh7 cells xenografted nude mice demonstrated that aminoquinol exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil with the combination treatment showed the highest therapeutic effect. Conclusion: The present study indicates for the first time the discovery of a new CDK4/6 and PI3K/AKT multi-kinase inhibitor aminoquinol. It could be used alone or as a combination therapeutic strategy for the treatment of HCC.