Polydatin Inhibits Hepatocellular Carcinoma Cell Proliferation and Sensitizes Doxorubicin and Cisplatin through Targeting Cell Mitotic Machinery

Polydatin (PD) is a natural compound with anticancer activities, but the underlying mechanisms remain largely unclear. To understand how PD inhibited hepatocellular carcinoma (HCC), we studied PD treatments in HCC HepG2 and SK-HEP1 cells, and normal liver HL-7702 cells. PD selectively blocked the proliferation of HCC cells but showed low toxicity in normal cells, while the effects of doxorubicin (DOX) and cisplatin (DDP) on HCC and normal liver cells were opposite. In the cotreatment studies, PD synergistically improved the inhibitory activities of DOX and DDP in HCC cells but alleviated their toxicity in HL-7702 cells. Furthermore, RNA-seq studies of PD-treated HepG2 cells revealed multiple altered signaling pathways. We identified 1679 Differentially Expressed Genes (DEGs) with over a 2.0-fold change in response to PD treatment. Integrative analyses using the DEGs in PD-treated HepG2 cells and DEGs in a TCGA dataset of HCC patients revealed five PD-repressed DEGs regulating mitotic spindle midzone formation. The expression of these genes showed significantly positive correlation with poor clinical outcomes of HCC patients, suggesting that mitotic machinery was likely a primary target of PD. Our findings improve the understanding of PD's anticancer mechanisms and provide insights into developing effective clinical approaches in HCC therapies.

Automated summary

Polydatin (PD) is a natural compound that has anticancer activities, but its mechanisms of action are not well understood. PD selectively inhibited the proliferation of hepatocellular carcinoma (HCC) cells while showing low toxicity in normal cells. Additionally, PD enhanced the inhibitory effects of doxorubicin (DOX) and cisplatin (DDP) in HCC cells and reduced their toxicity in normal liver cells. RNA-seq studies revealed multiple altered signaling pathways in PD-treated HCC cells, and the expression of PD-repressed genes correlated with poor clinical outcomes in HCC patients. These findings improve our understanding of PD's anticancer mechanisms and suggest potential clinical approaches for HCC therapies.