Ceramide Nanoliposomes Block Liver Tumors in Mouse Model

A nanoparticle delivery system was used to treat successfully a mouse model of human liver cancer by loading the cancer cells with the proapoptotic lipid, ceramide.

Liver cancer (hepatocellular carcinoma or HCC) is the fifth most common cancer in the world and is highly aggressive with five-year survivability in fewer than 5% of cases. Treatment is typically chemotherapy and surgical management including transplantation.

Ceramide is a bioactive lipid that has been implicated in a variety of physiological functions including apoptosis, cell growth arrest, differentiation, cell senescence, cell migration, and adhesion. Roles for ceramide and its downstream metabolites have also been suggested in a number of pathological states including cancer, neurodegeneration, diabetes, microbial pathogenesis, obesity, and inflammation. The substances that can cause ceramide to be generated tend to be stress signals that can cause the cells to go into programmed cell death. Ceramide thus acts as an intermediary that connects external signals to the internal metabolism of the cells.

Investigators at the Pennsylvania State University College of Medicine (Hershey, USA) evaluated the efficacy of nanoparticle liposomes (nanoliposomal C6-ceramide or cerosomes) containing C6-ceramide as a chemotherapeutic agent in a mouse model of human HCC. They first examined the effect of nanoliposomal C6-ceramide on in vitro cultures of human SK-HEP-1 cells by assessing cellular viability, caspase 3/7 activity, annexin-V expression, DNA fragmentation, cell cycle distribution, and AKT phosphorylation. SK-HEP-1 cells were then engrafted subcutaneously into athymic nude mice. Nanoliposomal C6-ceramide was administered by tail vein injection. Tumor size was monitored over time, followed by excision of tumors to evaluate tumor vascularization, proliferation, apoptosis, and cellular signaling.

Results reported in the December 30, 2010, online edition of the journal Gut revealed that nanoliposomal C6-ceramide, but not ghosts (nanoliposomes without ceramide) induced apoptotic cell death of SK-HEP-1 cells in vitro, concomitant with an accumulation of cells in the G2 phase of the cell cycle and decreased phosphorylation of AKT. Systemic administration of nanoliposomal C6-ceramide to mice engrafted with SK-HEP-1 tumors reduced tumor vascularization and proliferation, induced tumor cell apoptosis, decreased phosphorylation of AKT, and ultimately blocked tumor growth.

"Cerasomes were designed as a therapeutic alternative to common chemotherapeutics,” said contributing author Dr. Mark Kester, professor of pharmacology at Pennsylvania State University College of Medicine. "These have been shown to be toxic to cancer cells and not to normal cells, and have already been shown to effectively treat cellular and animal models of breast cancer and melanoma. Cerasomes have also been shown to be essentially free of toxic side effects normally associated with anticancer agents.”

"It is plausible that preventing liver tumor vascularization with cerasome treatment could induce widespread apoptosis, a genetically programmed series of events that leads to cell death in tumors,” said Dr. Kester. "The efficacy of our cerasomes in the treatment of diverse cancers lends significant therapeutic promise as it translates from bench to bedside.”

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Pennsylvania State University College of Medicine