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Novel ceramide analogs as potential chemotherapeutic agents in breast cancer.

Publication ,  Journal Article
Struckhoff, AP; Bittman, R; Burow, ME; Clejan, S; Elliott, S; Hammond, T; Tang, Y; Beckman, BS
Published in: J Pharmacol Exp Ther
May 2004

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.

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Published In

J Pharmacol Exp Ther

DOI

ISSN

0022-3565

Publication Date

May 2004

Volume

309

Issue

2

Start / End Page

523 / 532

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Tumor Cells, Cultured
  • Pharmacology & Pharmacy
  • Mitochondria
  • Humans
  • Epithelial Cells
  • Drug Resistance, Neoplasm
  • Ceramides
  • Cell Survival
  • Cell Death
 

Citation

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Struckhoff, A. P., Bittman, R., Burow, M. E., Clejan, S., Elliott, S., Hammond, T., … Beckman, B. S. (2004). Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J Pharmacol Exp Ther, 309(2), 523–532. https://doi.org/10.1124/jpet.103.062760
Struckhoff, Amanda P., Robert Bittman, Matthew E. Burow, Sanda Clejan, Steven Elliott, Timothy Hammond, Yan Tang, and Barbara S. Beckman. “Novel ceramide analogs as potential chemotherapeutic agents in breast cancer.J Pharmacol Exp Ther 309, no. 2 (May 2004): 523–32. https://doi.org/10.1124/jpet.103.062760.
Struckhoff AP, Bittman R, Burow ME, Clejan S, Elliott S, Hammond T, et al. Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J Pharmacol Exp Ther. 2004 May;309(2):523–32.
Struckhoff, Amanda P., et al. “Novel ceramide analogs as potential chemotherapeutic agents in breast cancer.J Pharmacol Exp Ther, vol. 309, no. 2, May 2004, pp. 523–32. Pubmed, doi:10.1124/jpet.103.062760.
Struckhoff AP, Bittman R, Burow ME, Clejan S, Elliott S, Hammond T, Tang Y, Beckman BS. Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J Pharmacol Exp Ther. 2004 May;309(2):523–532.

Published In

J Pharmacol Exp Ther

DOI

ISSN

0022-3565

Publication Date

May 2004

Volume

309

Issue

2

Start / End Page

523 / 532

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Tumor Cells, Cultured
  • Pharmacology & Pharmacy
  • Mitochondria
  • Humans
  • Epithelial Cells
  • Drug Resistance, Neoplasm
  • Ceramides
  • Cell Survival
  • Cell Death