PLANT-DERIVED MONOTERPENE SYNERGIZES WITH SORAFENIB TO SUPPRESS DRUG-TRIGGERED HEPATOCELLULAR CARCINOMA IN ANIMALS

Introduction and Objectives

Sorafenib (SB), while established as a first-line multikinase inhibitor for advanced hepatocellular carcinoma (HCC), demonstrates constrained clinical utility due to significant adverse effects and the emergence of drug resistance. To potentially enhance its therapeutic profile, we explored combination therapy with natural compounds. Previous investigations from our group identified safranal (SF), a major bioactive monoterpene constituent of saffron, as exhibiting notable anti-HCC properties.

This study aimed to investigate potential synergistic interactions between SB and SF that might improve HCC treatment outcomes.

Materials and Methods

We employed a chemically-induced cirrhotic HCC rat model to evaluate both SF monotherapy and SB-SF combination therapy. Comprehensive molecular characterization included RNA sequencing with subsequent differential gene expression analysis, pathway enrichment studies, and protein interaction network mapping. Mechanistic findings were confirmed through immunohistochemical and immunoblotting techniques.

Results

The SB-SF combination demonstrated enhanced anticancer efficacy compared to SB alone. Transcriptomic profiling identified 45 differentially expressed genes associated with HCC suppression, particularly those involved in proliferation control, oxidative stress response, and apoptotic regulation. The combination therapy significantly downregulated key oncogenic markers including NF-κB-p65, COX-2, and β-catenin, suggesting its potential as a cost-effective therapeutic approach that warrants further clinical investigation.

Conclusions

The study reveals a multifaceted mechanism by which SF augments SB's anticancer activity in HCC. The combined treatment modulates critical oncogenic pathways including NF-κB and Wnt/β-catenin signaling while rebalancing apoptotic regulators through decreased Bcl-2 and increased Bax/caspase expression. Additionally, it suppresses proliferative markers such as Ki-67 and PCNA while attenuating inflammatory mediators including TNF-α and MMP-9. These coordinated effects demonstrate potent anti-tumorigenic, anti-angiogenic, and pro-apoptotic activity, highlighting the therapeutic promise of this combination approach for HCC treatment.