Recombinant human acid sphingomyelinase as an adjuvant to sorafenib treatment of experimental liver cancer.

Abstract

BACKGROUND:

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the third leading cause of cancer death worldwide. The only approved systemic treatment for unresectable HCC is the oral kinase inhibitor, sorafenib. Recombinant human acid sphingomyelinase (rhASM), which hydrolyzes sphingomyelin to ceramide, is an orphan drug under development for the treatment of Type B Niemann-Pick disease (NPD). Due to the hepatotropic nature of rhASM and its ability to generate pro-apoptotic ceramide, this study evaluated the use of rhASM as an adjuvant treatment with sorafenib in experimental models of HCC.

METHODOLOGY/PRINCIPAL FINDINGS:

In vitro, rhASM/sorafenib treatment reduced the viability of Huh7 liver cancer cells more than sorafenib. In vivo, using a subcutaneous Huh7 tumor model, mouse survival was increased and proliferation in the tumors decreased to a similar extent in both sorafenib and rhASM/sorafenib treatment groups. However, combined rhASM/sorafenib treatment significantly lowered tumor volume, increased tumor necrosis, and decreased tumor blood vessel density compared to sorafenib. These results were obtained despite poor delivery of rhASM to the tumors. A second (orthotopic) model of Huh7 tumors also was established, but modest ASM activity was similarly detected in these tumors compared to healthy mouse livers. Importantly, no chronic liver toxicity or weight loss was observed from rhASM therapy in either model.

CONCLUSIONS/SIGNIFICANCE:

The rhASM/sorafenib combination exhibited a synergistic effect on reducing the tumor volume and blood vessel density in Huh7 xenografts, despite modest activity of rhASM in these tumors. No significant increases in survival were observed from the rhASM/sorafenib treatment. The poor delivery of rhASM to Huh7 tumors may be due, at least in part, to low expression of mannose receptors. The safety and efficacy of this approach, together with the novel findings regarding enzyme targeting, merits further investigation.

• Authors: Radoslav Savić, Xingxuan He, Isabel Fiel, Edward H Schuchman
• Journal: PloS one (PLoS One) Vol. 8 Issue 5 Pg. e65620 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23724146 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Neoplasm Proteins
• Phenylurea Compounds
• Recombinant Proteins
• Sphingolipids
• Niacinamide
• Sorafenib
• Sphingomyelin Phosphodiesterase

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Carcinoma, Hepatocellular (blood supply, drug therapy, genetics, pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chemotherapy, Adjuvant
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Liver Neoplasms (blood supply, drug therapy, genetics, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Neoplasm Proteins (genetics, metabolism)
• Niacinamide (analogs & derivatives, pharmacology, therapeutic use)
• Phenylurea Compounds (pharmacology, therapeutic use)
• Recombinant Proteins (pharmacology, therapeutic use)
• Signal Transduction (drug effects, genetics)
• Sorafenib
• Sphingolipids (metabolism)
• Sphingomyelin Phosphodiesterase (pharmacology, therapeutic use)
• Subcutaneous Tissue (drug effects, pathology)
• Survival Analysis
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays