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

Academic Article

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

  • 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
  • Kester, Mark
  • Status

    Publication Date

  • October 1, 2011
  • Published In

    Keywords

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Cell Line, Tumor
  • Ceramides
  • Deoxycytidine
  • Drug Carriers
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Enzyme Inhibitors
  • Female
  • Glucosyltransferases
  • Humans
  • Liposomes
  • MAP Kinase Signaling System
  • Mice
  • Mice, Nude
  • Morpholines
  • Nanoparticles
  • Pancreatic Neoplasms
  • Proto-Oncogene Proteins c-akt
  • Xenograft Model Antitumor Assays
  • Digital Object Identifier (doi)

    Start Page

  • 574
  • End Page

  • 585
  • Volume

  • 12
  • Issue

  • 7