These observations confirmed the pro-apoptotic and anti-pancreatic cancer effect of Lip-C6 is enhanced from the anti-metabolic action of gemcitibine or by avoiding ceramide metabolic process with gemcitabine and/or Lip-PDMP. More so, the efficacy of Lip-C6 in vivo in the xenograft model of pancreatic cancer was improved with gemcitabine. We efficiently employed an in vivo dose of gemcitabine in mice by way of tail vein injection that’s similar to the maximum tolerated dose in people . Then again, we employed a dose frequency of three times per week in contrast towards the single weekly dose made use of in people. Whilst this really is a probable downfall, it’s important to note that the charge of metabolism of gemcitabine in mice is substantially faster .44 Furthermore, our in vitro studies also indicated that a gemcitabine dose in combination with Lip-C6 may well be synergistically helpful whether or not decreased by 50-fold from your dose we made use of in vivo. Over the past a number of many years, sphingolipid metabolites have already been acknowledged for roles in modulating cell proliferation, apoptosis, cell migration and angiogenesis. Clinically, the concentration with the pro-apoptotic sphingolipid metabolite ceramide is considerably diminished in many different cancers which includes pancreatic and colon cancer.
45-47 Many different laboratories, including our own, have shown that improving endogenous ceramide syk kinase inhibitors levels through pharmacological or molecular approaches lead to cancer cell cytotoxicity.2,ten,11,45-48 Even so, these strategies are frequently constrained by drug efflux mechanisms and/or ceramide metabolism.21,22 A short while ago we have shown that the metabolism of exogenously delivered short-chain ceramide is cell sort dependent and concentration dependent.23 In PANC-1 cells high concentrations of C6-ceramide had been metabolized to glucosylceramide, a connected sphingolipid which is closely tied to multidrug resistance.23 This produces a selected issue for your use of C6-ceramide like a therapeutic for pancreatic cancer, however, one particular that could be conquer by inhibitors of glucosylceramide biosynthesis.
We also lately reported the in vitro efficacy of a nanoliposome recommended site incorporating the two C6-ceramide plus the glucosylceramide synthase inhibitor PDMP while in the treatment of neuroblastoma.31 In our current study, we employed this same combination-nanoliposome, Lip-C6/PDMP, within the treatment method of drug-resistant pancreatic cancer. With PDMP preventing the neutralization of ceramide to glucosylceramide , Lip-C6 was able to exert a robust toxicity in vitro towards PANC-1 cells. Not surprisingly, treatment in vitro with both Lip-C6/PDMP and gemcitabine, which augmented C6-ceramide and natural ceramide even more so, elicited an even greater induction of PANC-1 cell apoptosis. The advancement of Lip-C6/PDMP was not limited solely to improvement of Lip-C6 treatment, but additionally towards the ability to simultaneously deliver therapeutics in vivo in a non-toxic nanoscale formulation.
2,10,eleven In vivo, Lip-C6 alone was somewhat efficient despite the fact that the combinationnanoliposome Lip-C6/PDMP close to fully blocked PANC-1 tumor development.