Tran,three Todd E. Fox,three Brian M. Barth3 and Mark Kester3,* 1Departments of Medicine, 3Pharmacology and 4Surgery; Penn State School of Medication; 2Penn State Hershey Cancer Institute; Hershey, PA USA ; 5John Wayne Cancer Institute at Saint John?s Wellbeing Center; Santa Monica, CA USA Key words: ceramide, nanoliposome, gemcitabine, pancreatic cancer, glucosylceramide synthase, D-threo-PDMP, synergy, chemoresistance, apoptosis Abbreviations: PDMP, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol; Lip-Ghost, ghost nanoliposome; Lip-C6, C6-ceramide nanoliposome; Lip-PDMP, PDMP nanoliposome; Lip-C6/PDMP, C6-ceramide and PDMP nanolipososme; PKC, protein kinase C; TUNEL, terminal deoxynucleotidyl dUTP nick-end labeling; PEG, polyethylene glycol pro-apoptotic sphingolipid metabolite, ceramide, is endogenously created by chemo- or radio-therapies,5-7 and exogenous short-chain ceramide continues to be proven to augment chemotherapy- induced cytotoxicity.7-9 One on the interesting facets of working with ceramide as a chemotherapeutic may be the preferential selectivity for inducing apoptosis in cancer cells. For instance, we previously demonstrated that nanoliposomal C6-ceramide induces cell growth arrest and apoptosis in breast cancer cells and melanomas, but not non-transformed mammary gland epithelial cells or melanocytes.
2,10,11 Mechanisms underlying these observations are usually not completely understood, but may perhaps reflect decreased metabolic process within the nanoscale formulations in cancer cells and/ or enhanced promitogenic signaling in transformed cells. Particular promitogenic signaling read what he said cascades such as protein kinase C , Erk and Akt, are activated or overexpressed in several cancers.12-14 Mechanistically, ceramide forms structured membrane microdomains, recruiting PKC? to pre-formed Aktsignalsomes. 15 Ceramide-bound PKC? inactivates pro-survival Akt through phosphorylation at serine 34.15,sixteen In the equivalent scenario, we’ve proven that ceramide inhibits PKC?/Erk interactions.
17 Despite the elevated solubility of short-chain ceramide, its therapeutic efficacy is restricted as a consequence of its impermeability and to its tendency to precipitate in biological fluids. To improve solubility and to secure from metabolism, systemic delivery for ceramide has embraced nano ?remedies.? Latest reports have established the utility of Rosiglitazone ceramide delivery in nanoliposomes for that systemic therapy of breast cancer, hepatocellular carcinoma, large granular lymphocytic leukemia and melanoma animal models.two,10,11,18,19 The Nanotechnology Characterization Laboratory from the Nationwide Cancer Institute has just lately reported the pharmacokinetic profile, as well as lack of toxicology, of ceramide-enriched nanoliposomes . Additional limitations of ceramide as an anticancer therapeutic arises from metabolic process into pro-mitogenic phosphorylated derivatives , which are implicated in multidrug resistant cellular phenotypes.
20-22 Just lately, we have now shown that the fate of exogenously delivered C6-ceramide is cell style dependent and concentration dependent.23 By way of example, in PANC-1 cells, increased concentrations of C6-ceramide were preferentially metabolized to glucosylceramide, a lipid linked to multidrug resistant phenotypes.