ArticleThe Journal of pharmacology and experimental therapeutics2013
LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria.
Article in The Journal of pharmacology and experimental therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 52 citations in OpenAlex.
- Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.Cancer research · 2025Article
- Therapeutic Potential for Sphingolipids in Inflammatory Bowel Disease and Colorectal Cancer.Cancers · 2024Review
- Anti-ceramide antibody and sphingosine-1-phosphate as potential biomarkers of unresectable non-small cell lung cancer.Pathology oncology research : POR · 2024Article
- Therapeutic Potential of Ceramide in Cancer Treatment.Journal of cancer research and oncobiology · 2024Article
- A Ru(II)-Strained Complex with 2,9-Diphenyl-1,10-phenanthroline Ligand Induces Selective Photoactivatable Chemotherapeutic Activity on Human Alveolar Carcinoma Cells via Apoptosis.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells.Cancers · 2023Review
- Ceramide synthesis regulates biogenesis and packaging of exosomal MALAT1 from adipose derived stem cells, increases dermal fibroblast migration and mitochondrial function.Cell communication and signaling : CCS · 2023Article
- Antitumour Effects of Selected Pyridinium Salts on Sensitive Leukaemia HL60 Cells and Their Multidrug Resistant Topoisomerase II-Defective HL60/MX2 Counterparts.Molecules (Basel, Switzerland) · 2022Article
- Mitoquinol mesylate (MITOQ) attenuates diethyl nitrosamine-induced hepatocellular carcinoma through modulation of mitochondrial antioxidant defense systems.Toxicological research · 2022Article
- Targeting Sphingolipids for Cancer Therapy.Frontiers in oncology · 2021Review
- Pharmacological modulation of mitochondrial ion channels.British journal of pharmacology · 2019Review
- Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation.The Journal of biological chemistry · 2018Article
- Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq.Nature communications · 2018Article
- Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era.Advances in cancer research · 2018Review
- Sphingolipid metabolism in cancer signalling and therapy.Nature reviews. Cancer · 2018Review
- Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications.Chemical reviews · 2017Review
- Article
- Targeting reactive oxygen species in development and progression of pancreatic cancer.Expert review of anticancer therapy · 2017Review
- OPTIMIZATION OF SCALE-UP SYNTHESIS OF ANTI-CANCER CERAMIDE ANALOG 315.Journal of undergraduate chemistry research · 2017Article
- Treatment of a chemoresistant neuroblastoma cell line with the antimalarial ozonide OZ513.BMC cancer · 2016Article
Corrections and comments
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Authors and funding
16 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.