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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Novel Ceramide Analogs as Potential Chemotherapeutic Agents in Breast Cancer

Departments of Pharmacology (A.P.S., B.S.B.), Pathology (S.C.), and Medicine (T.H., M.E.B.), Molecular and Cellular Biology Program (M.E.B., S.C., S.E., Y.T., B.S.B.), Center for Bioenvironmental Research (M.E.B., S.C., S.E., Y.T., B.S.B.), Tulane Cancer Center (M.E.B., S.E., Y.T., B.S.B.), and Louisiana General Clinical Research Center (S.C.), Tulane University Health Sciences Center, New Orleans, Louisiana; Department of Chemistry and Biochemistry, Queens College, City University of New York, Flushing, New York (R.B.); and Veterans Affairs Medical Center, New Orleans, Louisiana (T.H.)

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)--resistant (IC₅₀ of 11.3 versus 32.9 µM) and TNF--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.

Address correspondence to: Dr. Barbara S. Beckman, Department of Pharmacology, Tulane Health Sciences Center, 1430 Tulane Ave. SL-83, New Orleans, LA 70112. E-mail: bbeckman{at}tulane.edu

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