Treatment of pancreatic cancer that cannot be surgically resected currently relies on cytotoxic chemotherapy with gemcitabine. Resistance to gemcitabine is nearly universal and appears to involve defects in the mitochondrial apoptotic pathway. The sphingolipid ceramide is a critical mediator of apoptosis, and insufficient ceramide accumulation has been linked to gemcitabine resistance. LCL-124 [((2S,3S,4E)-2-N-[6′-(1′′-pyridinium)-hexanoyl-sphingosine bromide] is a cationic ceramide that was effective in initiating apoptosis by causing mitochondrial depolarization in pancreatic cancer. LCL124 selectively accumulated and inhibited the growth of xenographs in vivo, and gemcitabine-resistant cells became more sensitive after treatment. These results suggest that this compound may be suited to overcome gemcitabine resistance.
See article at J Pharmacol Exp Ther 2013, 344:167–178.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics