Caffeine in the context of sorafenib chemotherapy: Insights from experimental hepatocarcinogenesis

Background: Hepatocellular carcinoma (HCC) features a high mortality burden worldwide, highlighting the need for improved therapeutic strategies. Caffeine (CAF), a widely consumed bioactive compound, has been reported to exert chemopreventive effects in HCC, but its interaction with standard therapies remains poorly explored. Purpose: We investigated whether CAF promotes the antitumoral effects of sorafenib (SOR) chemotherapy in HCC preclinical platforms. Study design: C3H/HeJ mice were submitted to diethylnitrosamine (DEN)-induced hepatocarcinogenesis and treated with CAF (50 mg/kg), SOR (30 mg/kg) or their combination for three weeks. C3A/LX2 spheroids and transwell co-cultures were also exposed to CAF, SOR or their combination at 1/5 or 1/10 of half maximal effective concentration. Results: The combination of CAF and SOR produced a synergistic reduction in tumor spheroid viability and inhibited HCC cell colony formation. Nonetheless, treatments exerted comparable effects on reducing liver tumor volume and Afp expression in vivo. Although only CAF+SOR reduced serum ALT levels and uniquely downregulated HCC-related Ccl3, treatments showed differential and subtle transcriptomic impacts during hepatocarcinogenesis - not showing promoting or additive effects when combined. Conclusion: In summary, while CAF potentiated SOR antitumoral activity in vitro, their combination did not lead to major effects in vivo, eliciting the need for further investigation.