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,inducing 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.
Highlights
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, with only 30–40% of the patients eligible for curative treatments at the time of disease diagnosis (Liu et al, 2015)
Using Western blotting analysis, we demonstrated that aminoquinol treatment significantly decreased the expressions of key proteins in the Cyclin-dependent kinases 4/6 (CDK4/6) as well as the PI3K/AKT pathways
The present study indicates for the first time that aminoquinol is a new CDK4/6 and PI3K/AKT multi-kinase inhibitor and a potential candidate drug for the treatment of human HCC
Summary
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, with only 30–40% of the patients eligible for curative treatments at the time of disease diagnosis (Liu et al, 2015). The multi-kinase inhibitor sorafenib has been used as the first-line agent in clinical practice since 2007. Another multiple kinase inhibitor lenvatinib was approved to be the first line treatment. Regorafenib and cabozantinib were recommended as second-line treatment for patients with advanced HCC who are resistant to sorafenib (Kudo 2020). The development of new and more effective therapies against HCC is urgently needed. 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. We identified a new CDK4/6 and PI3K/AKT multi-kinase inhibitor for the treatment of HCC
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