Anti-liver cancer therapeutic targets and safety of usenamine A in experimental liver cancer.

Background: Liver cancer is highly heterogeneous with poor drug response. Usenamine A has anticancer activity. Usnic acid has hepatocytotoxicity.

Objectives: As a derivative of usnic acid, if usenamine A can be safely used in treatment for liver cancer is unknown.

Methods: MTT and clone formation assays assessed cell viability and proliferation. Tumor growth was determined using a xenograft model. Flow cytometry was used to detect the cell cycle. mRNA transcriptome sequencing investigated differential gene expression. Safety was evaluated in mice.

Key Findings: Usenamine A inhibited proliferation and clone formation of HepG2 cells and xenograft tumor growth through cell cycle arrest at G0/G1. Usenamine A altered gene expression in a direction supporting anticancer activity. IL24, JUN, DUSP4, and DUSP5 were upregulated while PRKACA, PRKCB, TP53, WNT6, E2F3, LGR4, GPR78, and MAPK4 were downregulated. Ten of above genes overlapped in the KEGG enriched non-small cell lung cancer/glioma/cytokine-cytokine receptor interaction/Wnt/MAPK pathway network. Usenamine A has a strong binding affinity for PRKACA and PRKCB proteins. Usenamine A showed minimal toxicity in mice.

Conclusions: Usenamine A is a safe anticancer agent against hepatocellular carcinoma. Regulation of 12 cancer-associated genes and the correlated pathway network are its therapeutic targets.