title: Preclinical Evaluation of Liposomal C8 Ceramide as a Potent anti-Hepatocellular Carcinoma Agent.
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.
authors.affiliation: Department of Hyperbaric Oxygen, Lin Yi People's Hospital, Lin Yi, China.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Lv
authors.affiliation: Department of Oncology, Lin Yi People's Hospital, Lin Yi, China.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The Affiliated Hospital of Nanjing Medical University. Nanjing, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Oncology, Lin Yi People's Hospital, Lin Yi, China.
authors.forename: Yaoxia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Oncology, Lin Yi People's Hospital, Lin Yi, China.
authors.forename: Chenglin
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Oncology, Lin Yi People's Hospital, Lin Yi, China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of General Surgery, The Affiliated Hospital of Nanjing Medical University. Nanjing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Gui
authors.affiliation: Department of Oncology, Lin Yi People's Hospital, Lin Yi, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D008081:Liposomes; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C066099:2,3-N-octanoylsphingosine; D008081:Liposomes; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D048670:MAP Kinase Kinase 4; D013110:Sphingosine