title: Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer.
abstract: Poor prognosis cancers, such as pancreatic cancer, represent inherent challenges for ceramide-based nanotherapeutics due to metabolic pathways, which neutralize ceramide to less toxic or pro-oncogenic metabolites. We have recently developed a novel 80 nanometer diameter liposomal formulation that incorporates 30 molar percent C6-ceramide, a bioactive lipid that is pro-apoptotic to many cancer cells, but not to normal cells. In this manuscript, we evaluated the efficacy of combining nanoliposomal C6-ceramide (Lip-C6) with either gemcitabine or an inhibitor of glucosylceramide synthase. We first assessed the biological effect of Lip-C6 in PANC-1 cells, a gemcitabine-resistant human pancreatic cancer cell line, and found that low doses alone did not induce cell toxicity. However, cytotoxicity was achieved by combining Lip-C6 with either non-toxic sub-therapeutic concentrations of gemcitabine or with the glucosylceramide synthase inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Furthermore, these combinations with Lip-C6 cooperatively inhibited PANC-1 tumor growth in vivo. Mechanistically, Lip-C6 inhibited pro-survival Akt and Erk signaling, whereas the nucleoside analog gemcitabine did not. Furthermore, by including PDMP within the nanoliposomes, which halted ceramide neutralization as evidenced by LC-MS3, the cytotoxic effects of Lip-C6 were enhanced. Collectively, we have demonstrated that nanoliposomal ceramide can be an effective anti-pancreatic cancer therapeutic in combination with gemcitabine or an inhibitor of ceramide neutralization.
authors.affiliation: Department of Medicine, Penn State College of Medicine; Hershey, PA, USA.
authors.forename: Yixing
authors.initials: Y
authors.lastname: Jiang
authors.forename: Nicole A
authors.initials: NA
authors.lastname: DiVittore
authors.forename: James M
authors.initials: JM
authors.lastname: Kaiser
authors.forename: Sriram S
authors.initials: SS
authors.lastname: Shanmugavelandy
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Fritz
authors.forename: Yasser
authors.initials: Y
authors.lastname: Heakal
authors.forename: Hephzibah Rani S
authors.initials: HR
authors.lastname: Tagaram
authors.forename: Hua
authors.initials: H
authors.lastname: Cheng
authors.forename: Myles C
authors.initials: MC
authors.lastname: Cabot
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Staveley-O'Carroll
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Tran
authors.forename: Todd E
authors.initials: TE
authors.lastname: Fox
authors.forename: Brian M
authors.initials: BM
authors.lastname: Barth
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D008081:Liposomes / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D002518:Ceramides; D004337:Drug Carriers; D004791:Enzyme Inhibitors; D008081:Liposomes; D009025:Morpholines; D003841:Deoxycytidine; C033110:RV 538; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D051057:Proto-Oncogene Proteins c-akt; C504327:N-(alpha-hydroxyoctadecanoyl)phytosphingosine; D000093542:Gemcitabine