title: C6 ceramide sensitizes the anti-hepatocellular carcinoma (HCC) activity by AZD-8055, a novel mTORC1/2 dual inhibitor.
abstract: Aberrant activation of mammalian target of rapamycin (mTOR) plays pivotal roles in promoting hepatocellular carcinoma (HCC) tumorigenesis and chemoresistance. Here, we tested the potential anti-HCC activity by a novel mTOR complex 1/2 (mTORC1/2) dual inhibitor AZD-8055 and, more importantly, the potential AZD-8055 sensitization effect by a cell-permeable short-chain ceramide (C6). We showed that AZD-8055 mainly exerted moderate cytotoxic effect against a panel of HCC cell lines (HepG2, Hep3B, and SMMC-7721). Co-treatment of C6 ceramide remarkably augmented AZD-8055-induced HCC cytotoxicity. Meanwhile, C6 ceramide dramatically potentiated AZD-8055-induced HCC cell apoptotic death. Further studies demonstrated that AZD-8055 and C6 ceramide synergistically induced anti-survival and pro-apoptotic activity in primary cultured human HCC cells, but not in the non-cancerous human hepatocytes. Signaling studies showed that AZD-8055 and C6 ceramide synergistically suppressed Akt-mTOR complex 1/2 cascade activation. In vivo, AZD-8055 oral administration suppressed HepG2 hepatoma xenograft growth in nude mice, while moderately improving mice survival. Its anti-tumor activity was dramatically potentiated with co-administration of a liposome-packed C6 ceramide. Together, these results demonstrate that concurrent targeting mTORC1/2 by AZD-8055 exerts anti-tumor ability in preclinical HCC models, and its activity is further sensitized with co-administration of C6 ceramide.
authors.affiliation: Department of Intervention Radiology, The Affiliated Tumor Hospital of Xinjiang Medical University, 789 Suzhou Road, Urumqi, 830011, China.
authors.forename: Mo
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Intervention Radiology, The Affiliated Tumor Hospital of Xinjiang Medical University, 789 Suzhou Road, Urumqi, 830011, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Gu
authors.affiliation: Department of Cancer Research Institute, The Affiliated Tumor Hospital of Xinjiang Medical University, 789 Suzhou Road, Urumqi, 830011, China.
authors.forename: Wenjia
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Intervention Radiology, The Affiliated Tumor Hospital of Xinjiang Medical University, 789 Suzhou Road, Urumqi, 830011, China. proffanxiwen6@163.com.
authors.forename: Xiwen
authors.initials: X
authors.lastname: Fan
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000008:administration & dosage*; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D002518:Ceramides; D009025:Morpholines; D046912:Multiprotein Complexes; C101954:N-caproylsphingosine; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: AZD-8055; C6 ceramide; Chemo-sensitization; Hepatocellular carcinoma (HCC); Mammalian target of rapamycin (mTOR)