We have previously shown that Lip C6 can synergize and increase the activities of the Raf/Mek/Erk chemical sorafanib in melanoma models. 10 Likewise, it’s 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 Tipifarnib structure with printed literature, our present data demonstrate that the phosphorylation of Akt at serine 473 is not suffering from gemcitabine in pancreatic cancer cells. This is simply not surprising considering that, like a nucleoside analog, gemcitabines primary mechanism of action would be to interfere with DNA synthesis. Nevertheless, inhibition of Akt phosphorylation at 473 by Lip C6 led to a somewhat increased sensitivity to gemcitabine induced cytotoxicity in drug-resistant PANC 1 pancreatic cancer cells. Top C6 mediated reduction of Akt phosphorylation alone was Eumycetoma not adequate to produce cytotoxicity. From another perspective, it’s important to consider that the PANC 1 cell line, like several sophisticated cancer cell lines, may convert C6 ceramide to less-toxic and pro emergency metabolites. Studies have further suggested that gemcitabine itself can increase ceramide deposition. Within our research, therapy of PANC 1 cells using the triple combination of Lip C6, Lip PDMP, to block glucosylceramide synthase and gemcitabine significantly augmented the accumulation of normal ceramide variety and C6 ceramide. These observations established that the apoptotic and anti pancreatic cancer aftereffect of Lip C6 is improved by the anti metabolic activity of gemcitibine or by avoiding ceramide metabolic process with gemcitabine and/or Lip PDMP. Moreso, the efficacy of Lip C6 in vivo in a model of pancreatic cancer was increased with gemcitabine. We successfully employed an in vivo dose of gemcitabine in mice via tail vein injection that’s similar to the maximum Ibrutinib clinical trial tolerated dose in humans. Nevertheless, we used a dose volume of three times each week in contrast to the only weekly dose used in humans. While this is a potential downfall, it is very important to remember that the rate of conversion of gemcitabine in mice is faster. 44 Moreover, our in vitro studies also indicated a gemcitabine dose in mixture with Lip C6 may be synergistically effective even if paid off by 50-fold from the dose we found in vivo. Over the past several years, sphingolipid metabolites have been recognized for roles in modulating apoptosis, cell proliferation, cell migration and angiogenesis. Scientifically, the concentration of the pro apoptotic sphingolipid metabolite ceramide is notably reduced in numerous cancers including pancreatic and colon cancer. 45 47 Multiple laboratories, including our own, demonstrate that increasing endogenous ceramide amounts via pharmacological or molecular strategies lead to cancer cell cytotoxicity.