Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma
- Hephzibah Rani S Tagaram1,
- Nicole A DiVittore2,
- Brian M Barth2,
- James M Kaiser2,
- Diego Avella1,
- Eric T Kimchi1,
- Yixing Jiang3,
- Harriet C Isom4,
- Mark Kester2,
- Kevin F Staveley-O'Carroll1
- 1Department of Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
- 2Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
- 3Department of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
- 4Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
- Correspondence to Mark Kester, Departments of Pharmacology and of Cellular and Molecular Physiology, 500 University Drive, R130, P O Box 850, Hershey, PA 17033-0858, USA;
- Revised 8 October 2010
- Accepted 8 November 2010
- Published Online First 30 December 2010
Background and objectives Hepatocellular carcinoma (HCC) affects an increasing number of people worldwide. The poor survival rate of patients with HCC is manifested by an aggressive and metastatic phenotype, as well as a poor response to common therapeutic strategies. The purpose of this study was to evaluate the efficacy of nanoliposomal C6-ceramide as an antineoplastic agent in an in vivo model of human HCC.
Methods The growth-arresting and pro-apoptotic properties of nanoliposomal C6-ceramide were first evaluated in vitro in 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 and nanoliposomal C6-ceramide was administered by tail vein injection. Tumour size was monitored over time, followed by excision of tumours to evaluate tumour vascularisation, proliferation, apoptosis and cellular signalling.
Results Nanoliposomal C6-ceramide, but not ghost (no ceramide) nanoliposomes, 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 tumours reduced tumour vascularisation and proliferation, induced tumour cell apoptosis, decreased phosphorylation of AKT and ultimately blocked tumour growth.
Conclusions These studies show that nanoliposomal ceramide is an efficacious antineoplastic agent for the treatment of in vitro and in vivo models of human HCC.
Funding This work was funded in part by a Penn State Deans Feasibility Grant to HRT, by State of Pennsylvania non-formulary Tobacco Funds to MK, NIH R01 HL076789 to MK and K08 417-67HY to KFS.
Competing interests The Penn State Research Foundation has licensed ceramide nanoliposomes and other nonliposomal nanotechnology to Keystone Nano Inc (State College, PA). MK is the Chief Medical Officer of Keystone Nano Inc.
Provenance and peer review Not commissioned; externally peer reviewed.