Combining sorafenib with spermine and sphingosine synergistically enhances anticancer efficacy by modulating metabolic pathways and gut microbiome in hepatocellular carcinoma.

Spermine and sphingosine were identified from a microbiome metabolite library screen as candidates that boosted anticancer effects of sorafenib in HCC cell lines.

• Screening was performed against HepG2, Huh7, and SK-Hep-1 HCC cell lines.
• Both metabolites worked synergistically with sorafenib to suppress tumor growth.
• Testing was extended to patient-derived HCC organoids and a xenograft mouse model.
• Spermine and sphingosine are metabolites derived from the gut microbiome.

Spermine and sphingosine induced distinct cell cycle arrest patterns that contributed to increased apoptosis when combined with sorafenib.

• Spermine triggered cell cycle arrest at the S phase.
• Sphingosine and sorafenib induced G1 arrest.
• The combination contributed to an increased sub-G1 population, indicative of apoptosis.
• The combination promoted apoptosis in cultured HCC cells, patient-derived organoids, and xenograft models.

Sorafenib treatment led to the downregulation of key metabolic enzymes involved in spermine and sphingosine metabolism.

• SMOX, a key catabolic enzyme for spermine, was downregulated following sorafenib treatment.
• SPHK1 and CERS1, critical enzymes involved in sphingosine metabolism, were also downregulated by sorafenib.
• High expression levels of SMOX, SPHK1, and CERS1 are associated with poorer survival outcomes in liver cancer patients according to TCGA data.

Combination treatment of sorafenib with spermine or sphingosine altered the gut microbiome by increasing the relative abundance of Faecalibaculum.

• Analysis was performed using 16S rRNA sequencing in a xenograft mouse model.
• Increased relative abundance of Faecalibaculum was observed in the combination treatment groups.
• Faecalibaculum abundance was inversely correlated with tumor sizes in the xenograft mouse model.
• Faecalibaculum was proposed as a potential microbiome-based prognostic marker for HCC.

Hepatocellular carcinoma accounts for approximately 90% of liver cancer and is the third leading cause of cancer-related death.

• Sorafenib is a first-line multi-kinase inhibitor used in advanced HCC.
• Recent studies suggest that metabolites derived from the gut microbiome may offer new therapeutic opportunities for HCC.
• The study explored whether microbial metabolites could enhance the effectiveness of sorafenib.