We following evaluated improvements to Lip-C6 by inclusion of PDMP inside the exact same nanoliposome. A handle nanoliposomal formulation Lip-Ghost, Lip-C6 or Lip-C6/ PDMP, were routinely administered via tail-vein injection and tumor dimension was measured. We observed a modest antitumor impact from Lip-C6-treatment alone in addition to a robust result with Lip-C6/ PDMP . These benefits indicated that by expanding the intracellular concentration of endogenous ceramide, and by preventing the neutralization of exogenously delivered short-chain ceramide to glucosylceramide, a highly effective in vivo anti-pancreatic cancer result could possibly be accomplished. Discussion Whilst gemcitabine is considered to become just about the most successful drug in treating pancreatic cancer, resistance is usually observed as a result of mechanisms which include activation of NF?B, greater PI3 kinase exercise, plus a large basal degree of Akt phosphorylation.
38-40 We have now previously shown that Lip-C6 can synergize and augment the cytotoxic actions within the Raf/Mek/Erk inhibitor sorafanib in melanoma models.10 Likewise, it has been demonstrated that inhibition in the Akt/PI3 kinase pathway by compact molecules can synergize selleck chemical get more information with gemcitabine to induce apoptosis in diverse human pancreatic cancer cell lines.41-43 Consistent with published literature, our present data show that the phosphorylation of Akt at serine 473 is not affected by gemcitabine in pancreatic cancer cells. This is often not surprising considering that, as being a nucleoside analog, gemcitabine?s principal mechanism of action is always to interfere with DNA synthesis.
However, inhibition of Akt phosphorylation at serine 473 by Lip-C6 resulted in the appreciably greater sensitivity to gemcitabine-induced cytotoxicity in this content drug-resistant PANC-1 pancreatic cancer cells. Lip-C6-mediated reduction of Akt phosphorylation alone was not sufficient to induce cytotoxicity. From a further point of view, it is very important contemplate the PANC-1 cell line, like quite a few state-of-the-art cancer cell lines, can convert C6-ceramide to significantly less toxic and pro-survival metabolites. Scientific studies have even further suggested that gemcitabine itself can encourage ceramide accumulation. In our research, treatment of PANC-1 cells with the triple blend of Lip-C6, Lip-PDMP, to block glucosylceramide synthase and gemcitabine substantially augmented the accumulation of C6-ceramide and natural ceramide species.