Novel ceramide analogs as potential chemotherapeutic agents in breast cancer.

Abstract

Recent evidence suggests a role for aberrant ceramide levels in the pathogenesis of cancer and chemoresistance and indicates that manipulation of tumor ceramide levels may be a useful strategy in the fight against breast cancer. This study demonstrates that alterations in the degree and position of unsaturation of bonds in the sphingoid backbone of d-erythro-N-octanoyl-sphingosine (Cer) affect the antiproliferative ability of ceramide analogs in breast cancer cells. The most potent analog of Cer we tested is (2S,3R)-(4E,6E)-2-octanoylamidooctadecadiene-1,3-diol (4,6-diene-Cer), which contains an additional trans double bond at C(6)-C(7) of the sphingoid backbone. 4,6-Diene-Cer exhibited higher potency than Cer in tumor necrosis factor (TNF)-alpha-resistant (IC(50) of 11.3 versus 32.9 microM) and TNF-alpha-sensitive (IC(50) of 13.7 versus 37.7 microM) MCF-7 cells. 4,6-Diene-Cer was also more potent than Cer in inducing cell death in MDA-MB-231 and NCI/ADR-RES breast cancer cell lines (IC(50) of 3.7 versus 11.3 microM, and 24.1 versus 86.9 microM, respectively). 4,6-Diene-Cer caused a prolonged elevation of intracellular ceramide levels in MCF-7 cells, which may contribute to its enhanced cytotoxicity. Furthermore, treatment of MCF-7 cells with Cer or 4,6-diene-Cer resulted in induction of apoptosis by 8 h via the mitochondrial pathway, as demonstrated by release of cytochrome c, loss of membrane asymmetry (measured by Annexin V staining), and a decrease in the mitochondrial membrane potential. Importantly, both Cer and 4,6-diene-Cer displayed selectivity toward transformed breast cells over nontransformed breast epithelial cells. These data suggest that these and other novel ceramide analogs represent potential therapeutic agents in breast cancer treatment.

• Authors: Amanda P Struckhoff, Robert Bittman, Matthew E Burow, Sanda Clejan, Steven Elliott, Timothy Hammond, Yan Tang, Barbara S Beckman
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 309 Issue 2 Pg. 523-32 (May 2004) ISSN: 0022-3565 [Print] United States
• PMID: 14742741 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 2-octanoylamido-4,6-octadecadiene-1,3-diol
• Antineoplastic Agents
• Ceramides
• Tumor Necrosis Factor-alpha

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Breast Neoplasms (pathology)
• Cell Death (drug effects)
• Cell Survival (drug effects)
• Ceramides (chemistry, pharmacology)
• Drug Resistance, Neoplasm
• Epithelial Cells (drug effects)
• Humans
• Mitochondria (drug effects, physiology)
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (pharmacology)