Abstract
Purpose
Resistance to endocrine and chemotherapies remains the primary cause of breast cancer treatment failure. We have synthesized four novel d-erythro N-octanoyl sphingosine analogs and catalogued their activity in drug-sensitive (MCF-7), endocrine-resistant (MDA-MB-231) and chemoresistant (MCF-7TN-R) breast cancer cells.
Methods
3-(4,5-Dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine cell viability; colony assay was performed to determine effects on clonogenic survival and 1H NMR, 13C NMR, HPLC spectra and elemental analytical data analyses were used to determine analog identity and purity.
Results
All four analogs inhibited both viability and clonogenic survival, with analog C exhibiting a log-fold improvement in anti-survival activity compared to the parent compound.
Conclusion
With resistance to current breast cancer chemotherapies on the rise, the development of novel therapeutic targets is of growing importance. Our results show that lipid analogs have therapeutic potential in treating chemo- and endocrine-resistant breast cancer.
This is a preview of subscription content, log in via an institution to check access.
References
American Cancer Society (2009) Cancer facts and figures 2009. American Cancer Society, Atlanta
Liu YY, Han TY, Giuliano AE, Cabot MC (1999) Expression of glucosylceramide synthase, converting ceramide to glucosylceramide, confers adriamycin resistance in human breast cancer cells. J Biol Chem 274:1140–1146
Liu YY, Yu JY, Yin D, Patwardhan GA, Gupta V, Hirabayashi Y, Holleran WM, Giuliano AE, Jazwinski SM, Gouaze-Andersson V, Consoli DP, Cabot MC (2008) A role for ceramide in driving cancer cell resistance to doxorubicin. Faseb J 22:2541–2551
Qiu L, Zhou C, Sun Y, Di W, Scheffler E, Healey S, Wanebo H, Kouttab N, Chu W, Wan Y (2006) Paclitaxel and ceramide synergistically induce cell death with transient activation of EGFR and ERK pathway in pancreatic cancer cells. Oncol Rep 16:907–913
Simstein R, Burow M, Parker A, Weldon C, Beckman B (2003) Apoptosis, chemoresistance, and breast cancer: insights from the MCF-7 cell model system. Exp Biol Med (Maywood) 228:995–1003
Bielawska A, Linardic CM, Hannun YA (1992) Modulation of cell growth and differentiation by ceramide. FEBS Lett 307:211–214
Obeid LM, Linardic CM, Karolak LA, Hannun YA (1993) Programmed cell death induced by ceramide. Science 259:1769–1771
Ogretmen B (2006) Sphingolipids in cancer: regulation of pathogenesis and therapy. FEBS Lett 580:5467–5476
Saddoughi SA, Song P, Ogretmen B (2008) Roles of bioactive sphingolipids in cancer biology and therapeutics. Subcell Biochem 49:413–440
Venable ME, Webb-Froehlich LM, Sloan EF, Thomley JE (2006) Shift in sphingolipid metabolism leads to an accumulation of ceramide in senescence. Mech Ageing Dev 127:473–480
Antoon JW, Liu J, Gestaut MM, Burow ME, Beckman BS, Foroozesh M (2009) Design, synthesis, and biological activity of a family of novel ceramide analogues in chemoresistant breast cancer cells. J Med Chem 52:5748–5752
Struckhoff AP, Bittman R, Burow ME, Clejan S, Elliott S, Hammond T, Tang Y, Beckman BS (2004) Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J Pharmacol Exp Ther 309:523–532
Acknowledgments
We thank Dr. James Robinson’s laboratory at Tulane for help in quantifying viability results. This research was supported by a grant from the Louisiana Cancer Research Consortium (#631324).
Conflict of interest statement
None.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Antoon, J.W., Liu, J., Ponnapakkam, A.P. et al. Novel d-erythro N-octanoyl sphingosine analogs as chemo- and endocrine-resistant breast cancer therapeutics. Cancer Chemother Pharmacol 65, 1191–1195 (2010). https://doi.org/10.1007/s00280-009-1233-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-009-1233-0