Dicoumarol suppresses intrahepatic cholangiocarcinoma growth via modulation of the PI3K/Akt signaling pathway.

Abstract

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy after hepatocellular carcinoma (HCC), characterized by high invasiveness and poor clinical prognosis. Dicoumarol (Dic) is a naturally occurring coumarin compound that was previously used clinically as an anticoagulant. In recent years, increasing attention has been given to its potential antitumor effects. This study aimed to investigate the antitumor effect of the natural compound Dic in ICC and its underlying molecular mechanisms. Our results demonstrated that Dic significantly inhibited the proliferation, migration, and invasion of ICC cells in vitro while promoting apoptosis. In vivo, Dic markedly reduced tumor burden in a murine ICC model without causing obvious hepatotoxicity, suggesting acceptable tolerability under the therapeutic dosing regimen used in this study. RNA-seq identified a total of 1374 differentially expressed genes (DEGs) following Dic treatment, and KEGG pathway analysis revealed alterations in multiple cancer-related pathways, including PI3K/Akt signaling. Western blot analysis further confirmed that Dic significantly inhibited Akt phosphorylation in both ICC cells and tumor tissues, corroborating the suppression of PI3K/Akt signaling by Dic. This study provides new experimental evidence for the potential of Dic in the treatment of ICC and supports further investigation of Dic as a potential therapeutic candidate for ICC.