Lactate transport inhibition for treatment of hepatocellular carcinoma in an N1S1 tumor model

Hepatocellular carcinoma uses both aerobic and anaerobic metabolism (glycolysis). Glycolysis is inhibited by elevated intracellular lactate levels. This study evaluates dual metabolic inhibition by transarterial embolization (TAE) with two lactate transport inhibitors, caffeic acid or ferulic acid, in an N1-S1 hepatocellular carcinoma in a rat model. 24 rats with implanted liver N1S1 tumors were divided into 4 groups: control group (n=5, 1 mL normal saline, NS), bland embolization group (TAE, n=4, 10 mg 50-150 micron PVA in 1 mL NS), TAE and caffeic acid group (TAE+CA, n=5, 10mg PVA and 30 mg of caffeic acid in 1 mL NS), and TAE and ferulic acid group (TAE+FA, n=5, 10 mg PVA and 30 mg ferulic acid in 1 mL NS). Embolization was through retrograde catheterization of the gastroduodenal artery and verified through contrast-enhanced ultrasound (CE-US). Tumor volume was measured by US before and twice a week until 4 weeks post-treatment. The repeated measures ANOVA was used to compare differences in pre-treatment tumor volume by group and over time. At 4 weeks, the rats were sacrificed and histopathologic evaluation performed. There was no significant difference in the initial tumor sizes between each group. The control group showed rapid growth with a volume that was 3,000% larger compared with baseline. In the TAE group, tumor volume increased when compared to pre-treatment volume by 6.7 +/-11.2%. Both TAE+CA and TAE+FA demonstrated a statistically significant decrease in tumor size when compared to TAE with a decrease in tumor volume by 86.8+/-10.2% and 71.8+/-10.5%, respectively (p<0.0001). Histopathogic evaluation showed marked decreases in amounts of residual tumor and inflammatory changes in the caffeic acid and ferulic acid groups when compared to the TAE group. Embolization with PVA and caffeic acid or ferulic acid provides a statistically significant improved tumor response compared to PVA alone in a rat N1S1 tumor model. Combination treatment through inhibition of both aerobic metabolism through embolization and inhibtion of anaerobic metabolism through lactate transport inhibition is a viable and effective treatment approach that shows great promise.