New therapeutic modalities delivering potent anti-neoplastic agents that target pro-survival signaling cascades may turn out to be an important therapeutic modality. The use of pro-apoptotic age
nts, for instance ceramide which preferentially induces apoptosis in transformed cells, could possibly of fer the potential to enhance the efficacy of present treatments with no even further exacerbating toxicities.2,3 Furthermore, delivering these agents inside of nanoscale packages has the possible to conquer mechanisms of multidrug resistance.four Sphingolipids happen to be recognized as significant lipidbased mediators of cell growth, death and differentiation. The Bad prognosis cancers, like pancreatic cancer, signify inherent issues for ceramide-based nanotherapeutics on account of metabolic pathways which neutralize ceramide to significantly less toxic or pro-oncogenic metabolites. We have recently produced a novel 80 nanometer diameter liposomal formulation that incorporates 30 molar % C6-ceramide, a bioactive lipid that’s pro-apoptotic to a lot of cancer cells, but to not typical cells.
On this manuscript, we evaluated the efficacy of combining nanoliposomal C6-ceramide with either gemcitabine or an inhibitor of glucosylceramide synthase. We very first assessed the biological impact of Lip-C6 in PA NC-1 cells, a gemcitabine-resistant human pancreaPF-05212384 tic cancer cell line, and located that lower doses alone did not induce cell toxicity. Then again, cytotoxicity was accomplished by combining Lip-C6 with both non-toxic sub-therapeutic concentrations of gemcitabine or with the glucosylceramide synthase inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol . Moreover, these combinations with Lip-C6 cooperatively inhibited PA NC-1 tumor development in vivo. Mechanistically, Lip-C6 inhibited pro-survival Akt and Erk signaling, whereas the nucleoside analog gemcitabine didn’t.
Additionally, by such as Ppenlac DMP within the nanoliposomes, which halted ceramide neutralization as evidenced by LC-MS/MS/MS, the cytotoxic effects of Lip-C6 were enhanced. Collectively, we’ve demonstrated that nanoliposomal ceramide could very well be an effective anti-pancreatic cancer therapeutic in combination with gemcitabine or an inhibitor of ceramide neutralization. Combinatorial therapies increase the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer Yixing Jiang,1,2 Nicole A. DiVittore,2,3 James M. Kaiser,3 Sriram S. Shanmugavelandy,3 Jennifer L. Fritz,three Yasser Heakal,3 Hephzibah Rani S. Tagaram,four Hua Cheng,one,2 Myles C. Cabot,5 Kevin F. Staveley-O?Carroll,4 Melissa A.