Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer

• Published in: Cancer biology & therapy 2011-10, Vol.12 (7), p.574-585
• Main Authors: Jiang, Yixing, DiVittore, Nicole A., Kaiser, James M., Shanmugavelandy, Sriram S., Fritz, Jennifer L., Heakal, Yasser, Tagaram, Hephzibah Rani S., Cheng, Hua, Cabot, Myles C., Staveley-O'Carroll, Kevin F., Tran, Melissa A., Fox, Todd E., Barth, Brian M., Kester, Mark
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cell Line, Tumor; Ceramides - administration & dosage; Ceramides - pharmacokinetics; Ceramides - pharmacology; Cycle; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Drug Carriers - therapeutic use; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Inhibitors - pharmacology; Female; Glucosyltransferases - antagonists & inhibitors; Humans; Landes; Liposomes - therapeutic use; MAP Kinase Signaling System - drug effects; Mice; Mice, Nude; Morpholines - administration & dosage; Morpholines - pharmacology; Nanoparticles - administration & dosage; Nanoparticles - therapeutic use; Organogenesis; Pancreatic Neoplasms - drug therapy; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Research Paper; Xenograft Model Antitumor Assays
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.12.7.15971

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.