Back to Search
Start Over
Preclinical Evaluation of Liposomal C8 Ceramide as a Potent anti-Hepatocellular Carcinoma Agent
- Source :
- PLoS ONE, PLoS ONE, Vol 11, Iss 1, p e0145195 (2016)
- Publication Year :
- 2016
- Publisher :
- Public Library of Science, 2016.
-
Abstract
- Hepatocellular carcinoma (HCC) remains a global health threat. The search for novel anti-HCC agents is urgent. In the current study, we synthesized a liposomal C8 ceramide, and analyzed its anti-tumor activity in pre-clinical HCC models. The liposomal C8 (ceramide) potently inhibited HCC cell (HepG2, SMMC-7721 and Huh-7 lines) survival and proliferation, more efficiently than free C8 ceramide. Yet, non-cancerous HL7702 human hepatocytes were resistant to the liposomal C8 treatment. Liposomal C8 activated caspase-dependent apoptosis in HCC cells, and HCC cytotoxicity by liposomal C8 was significantly attenuated with co-treatment of caspase inhibitors. At the molecular level, we showed that liposomal C8 activated ASK1 (apoptosis signal-regulating kinase 1)-JNK (Jun N-terminal protein kinase) signaling in HCC cells. On the other hand, JNK pharmacological inhibition or dominant negative mutation, as well as ASK1 shRNA-knockdown remarkably inhibited liposomal C8-induced apoptosis in HCC cells. Further studies showed that liposomal C8 inhibited AKT-mTOR (mammalian target of rapamycin) activation in HCC cells. Restoring AKT-mTOR activation by introducing a constitutively-active AKT alleviated HepG2 cytotoxicity by liposomal C8. In vivo, intravenous (i.v.) injection of liposomal C8 significantly inhibited HepG2 xenograft growth in severe combined immuno-deficient (SCID) mice, and mice survival was significantly improved. These preclinical results suggest that liposomal C8 could be further studied as a valuable anti-HCC agent.
- Subjects :
- 0301 basic medicine
Male
Ceramide
Carcinoma, Hepatocellular
MAP Kinase Kinase 4
Cell
lcsh:Medicine
Apoptosis
Mice, SCID
Pharmacology
Biology
MAP Kinase Kinase Kinase 5
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Sphingosine
Cell Line, Tumor
medicine
Animals
Humans
ASK1
MTT assay
Cytotoxicity
lcsh:Science
Protein kinase B
Cell Proliferation
Multidisciplinary
Cell growth
lcsh:R
Liver Neoplasms
digestive system diseases
Enzyme Activation
030104 developmental biology
medicine.anatomical_structure
chemistry
030220 oncology & carcinogenesis
Liposomes
Cancer research
lcsh:Q
Drug Screening Assays, Antitumor
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....07543632360920eefefb197166300809