Treatment of
pancreatic cancer that cannot be surgically resected currently relies on minimally beneficial cytotoxic
chemotherapy with
gemcitabine. As the fourth leading cause of
cancer-related death in the United States with dismal survival statistics,
pancreatic cancer demands new and more effective treatment approaches. Resistance to
gemcitabine is nearly universal and appears to involve defects in the intrinsic/mitochondrial apoptotic pathway. The bioactive
sphingolipid ceramide is a critical mediator of apoptosis initiated by a number of therapeutic modalities. It is noteworthy that insufficient
ceramide accumulation has been linked to
gemcitabine resistance in multiple
cancer types, including
pancreatic cancer. Taking advantage of the fact that
cancer cells frequently have more negatively charged mitochondria, we investigated a means to circumvent resistance to
gemcitabine by targeting delivery of a cationic
ceramide (l-t-C6-CCPS [
LCL124: ((2S,3S,4E)-2-N-[6'-(1″-pyridinium)-hexanoyl-
sphingosine bromide)]) to
cancer cell mitochondria.
LCL124 was effective in initiating apoptosis by causing mitochondrial depolarization in
pancreatic cancer cells but demonstrated significantly less activity against nonmalignant pancreatic ductal epithelial cells. Furthermore, we demonstrate that the mitochondrial membrane potentials of the
cancer cells were more negative than nonmalignant cells and that dissipation of this potential abrogated cell killing by
LCL124, establishing that the effectiveness of this compound is potential-dependent.
LCL124 selectively accumulated in and inhibited the growth of xenografts in vivo, confirming the
tumor selectivity and therapeutic potential of cationic
ceramides in
pancreatic cancer. It is noteworthy that
gemcitabine-resistant
pancreatic cancer cells became more sensitive to subsequent treatment with
LCL124, suggesting that this compound may be a uniquely suited to overcome
gemcitabine resistance in
pancreatic cancer.