title: LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Beckham
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Jones
authors.forename: Tucker
authors.initials: T
authors.lastname: Marrison
authors.forename: Clayton S
authors.initials: CS
authors.lastname: Lewis
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cheng
authors.forename: Venkat K
authors.initials: VK
authors.lastname: Ramshesh
authors.forename: Gyda
authors.initials: G
authors.lastname: Beeson
authors.forename: Craig C
authors.initials: CC
authors.lastname: Beeson
authors.forename: Richard R
authors.initials: RR
authors.lastname: Drake
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.forename: Zdzislaw M
authors.initials: ZM
authors.lastname: Szulc
authors.forename: Besim
authors.initials: B
authors.lastname: Ogretmen
authors.forename: James S
authors.initials: JS
authors.lastname: Norris
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles; D015153:Blotting, Western; D002232:Carbocyanines; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004396:Coloring Agents; D045304:Cytochromes c / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000473:pathology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013057:Spectrum Analysis; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C578459:2-N-(6'-(1'-pyridinium)hexanoyl)sphingosine; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002232:Carbocyanines; D002518:Ceramides; D004396:Coloring Agents; D003841:Deoxycytidine; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D045304:Cytochromes c; D000093542:Gemcitabine