RT Journal Article
SR Electronic
T1 Novel Ceramide Analogs as Potential Chemotherapeutic Agents in Breast Cancer
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 523
OP 532
DO 10.1124/jpet.103.062760
VO 309
IS 2
A1 Struckhoff, Amanda P.
A1 Bittman, Robert
A1 Burow, Matthew E.
A1 Clejan, Sanda
A1 Elliott, Steven
A1 Hammond, Timothy
A1 Tang, Yan
A1 Beckman, Barbara S.
YR 2004
UL http://jpet.aspetjournals.org/content/309/2/523.abstract
AB 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)-α-resistant (IC50 of 11.3 versus 32.9 μM) and TNF-α-sensitive (IC50 of 13.7 versus 37.7 μM) 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 (IC50 of 3.7 versus 11.3 μM, and 24.1 versus 86.9 μM, 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. The American Society for Pharmacology and Experimental Therapeutics