Recombinant Human Acid Sphingomyelinase as an Adjuvant to Sorafenib Treatment of Experimental Liver Cancer

摘要: Background Hepatocellular carcinoma (HCC) is the most common form of liver cancer and third leading cause death worldwide. The only approved systemic treatment for unresectable HCC oral kinase inhibitor, sorafenib. Recombinant human acid sphingomyelinase (rhASM), which hydrolyzes sphingomyelin to ceramide, an orphan drug under development Type B Niemann-Pick disease (NPD). Due hepatotropic nature rhASM its ability generate pro-apoptotic this study evaluated use as adjuvant with sorafenib in experimental models HCC. Methodology/Principal Findings In vitro, rhASM/sorafenib reduced viability Huh7 cells more than In vivo, using a subcutaneous tumor model, mouse survival was increased proliferation tumors decreased similar extent both groups. However, combined significantly lowered volume, necrosis, blood vessel density compared These results were obtained despite poor delivery tumors. A second (orthotopic) model also established, but modest ASM activity similarly detected these healthy livers. Importantly, no chronic toxicity or weight loss observed from therapy either model. Conclusions/Significance The combination exhibited synergistic effect on reducing volume xenografts, No significant increases treatment. may be due, at least part, low expression mannose receptors. safety efficacy approach, together novel findings regarding enzyme targeting, merits further investigation.