Integration of Ethanol and the Immune Modulator Curcumin for Immuno-Ablation of Hepatocellular Carcinoma

Purpose Immuno-ethanol ablation using an ethanol and immune adjuvant formulation is investigated as a potent immuno-ablation approach that can achieve an enhanced anti-cancer effect in the treatment of hepatocellular carcinoma (HCC). Materials and Methods Ethanol concentration- and exposure time-dependent cellular responses were investigated. Curcumin was combined with ethanol as an immuno-ablation agent. Cellular uptake of curcumin, cancer cell killing, and inflammatory markers of ethanol-curcumin treatment were characterized. To evaluate the potential in vivo anti-cancer immunity of ethanol-curcumin treatment, each right and left lobe of rat liver was concurrently inoculated with N1S1 HCC cells and a mixture of treated N1S1 cells (ethanol only or ethanol-curcumin) in Sprague Dawley rats (Each group: 5 rats, Control: non-treated N1S1 cells). Tumor growth and immune response were characterized with 7T MRI, flowcytometry analysis, and immunohistology. Results An optimized ethanol-curcumin (10% ethanol and 0.5% w/v curcumin solution) treatment contributed to an enhanced cellular uptake of curcumin, increased cancer cell killing, and decreased inflammatory reaction. Ethanol-curcumin treated N1S1 cell implantation in the rat liver demonstrated N1S1 HCC tumor rejection. The secondary tumor growth by non-treated N1S1 cell inoculation was significantly suppressed at the same time. Activated anti-cancer immunity was evidenced by significantly increased CD8+ T cell infiltration (3.5-fold) and CD8+/Treg ratio (4.5-fold) in the experimental group compared to the control group. Conclusion Enhanced anti-cancer effect of immuno-ethanol ablation could be achieved with ethanol-curcumin agent. The results underscore the importance of optimized immuno-ablation therapeutic procedures for the enhanced therapeutic outcomes.