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Abstract

Hepatocellular carcinoma (HCC) is one of the most common and aggressive subtypes of liver cancer. It has a poor prognosis, a high rate of recurrence and shows limited response to current therapies. In order to combat this condition, the use of natural products as multitarget anticancer agents is gaining momentum. In this study, we investigated the medicinal value of bisbenzylisoquinoline (BBI) alkaloids from the Stephania genus via an integrative in silico approach. Due to their improved pharmacokinetic profiles and expected low toxicity, we chose 11 BBI derivatives. Network pharmacology analysis revealed 334 overlapped targets between the compounds and HCC. Functional enrichment indicated that the PI3K-Akt signaling pathway was essential in HCC progression. In addition, protein-protein interaction (PPI) network construction and topological analysis identified AKT1 and PI3K as hub proteins. Molecular docking simulations found that isotrilobine had the highest binding affinity towards both AKT1 (-10.5 kcal/mol) and PI3K (-9.9 kcal/mol), compared to that of the reference drug sorafenib. These findings indicated a possible involvement of BBI compounds in modulating key oncogenic pathways relevant to tumor growth and metastasis. Taken together, this study unveils isotrilobine as a promising lead compound and provides a mechanistic rationale for the further exploration of Stephania-derived BBI alkaloids as potential HCC therapeutics.

Keywords

Bisbenzylisoquinolines, Hepatocellular carcinoma, Molecular docking, Network pharmacology, Stephania

Subject Area

Chemistry

Article Type

Article

First Page

1442

Last Page

1454

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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