1. Preclinical Evaluation of Liposomal C8 Ceramide as a Potent anti-Hepatocellular Carcinoma Agent
- Author
-
Zhongmin Zhang, Xiaoyu Wu, Xin Wang, Chenglin Li, Weihong Gong, Liang Gui, Huiqing Lv, and Yaoxia Wang
- 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 - 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.
- Published
- 2016