We’ve previously found that Lip C6 can synergize and augment the cytotoxic actions of the Raf/Mek/Erk chemical sorafanib in cancer designs. 10 Likewise, it has been demonstrated that inhibition of the Akt/PI3 kinase pathway by small molecules can synergize with gemcitabine to induce apoptosis in a variety of human pancreatic cancer cell lines. 41 43 Consistent order Decitabine with printed literature, our current data demonstrate that the phosphorylation of Akt at serine 473 is not suffering from gemcitabine in pancreatic cancer cells. This is not surprising due to the fact, being a nucleoside analog, gemcitabines primary mechanism of action would be to restrict DNA synthesis. But, inhibition of Akt phosphorylation at serine 473 by Lip C6 resulted in a significantly enhanced sensitivity to gemcitabine induced cytotoxicity in drug resistant PANC 1 pancreatic cancer cells. Top C6 mediated reduction of Akt phosphorylation alone was haematopoietic stem cells perhaps not sufficient to induce cytotoxicity. From yet another perspective, it is important to consider the PANC 1 cell line, like many high level cancer cell lines, can convert C6 ceramide to less-toxic and professional success metabolites. Studies have further proposed that gemcitabine itself may promote ceramide accumulation. In our study, therapy of PANC 1 cells with the triple mixture of Lip C6, Lip PDMP, to block glucosylceramide synthase and gemcitabine significantly enhanced the accumulation of natural ceramide species and C6 ceramide. These findings established the apoptotic and anti pancreatic cancer aftereffect of Lip C6 is improved by the anti metabolic activity of gemcitibine or by stopping ceramide kcalorie burning with gemcitabine and/or Lip PDMP. Moreso, the efficacy of Lip C6 in vivo in a model of pancreatic cancer was enhanced with gemcitabine. We successfully employed an in vivo dose of gemcitabine in mice via tail vein injection that is like the maximum Imatinib STI-571 tolerated dose in humans. However, we used a dose volume of three times each week in contrast to the single weekly dose used in humans. While this is a potential downfall, it’s important to note that the metabolic rate of gemcitabine in mice is considerably faster. 44 Moreover, our in vitro studies also indicated that a dose in mixture with Lip C6 might be synergistically effective even when paid off by 50 fold from the dose we utilized in vivo. Within the last several years, sphingolipid metabolites have been recognized for roles in modulating apoptosis, cell proliferation, cell migration and angiogenesis. Technically, the focus of the professional apoptotic sphingolipid metabolite ceramide is significantly paid off in multiple cancers including pancreatic and colon cancer. 45 47 Multiple laboratories, including our own, have shown that increasing endogenous ceramide amounts via pharmacological or molecular strategies result in cancer cell cytotoxicity.