Novel D: -erythro N-octanoyl sphingosine analogs as chemo- and endocrine-resistant breast cancer therapeutics.
OBJECTIVE
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 (1)H NMR, (13)C 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.


CONCLUSIONS
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.
Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
James W
JW
Antoon
Jiawang
J
Liu
Adharsh P
AP
Ponnapakkam
Matthew M
MM
Gestaut
Maryam
M
Foroozesh
Barbara S
BS
Beckman
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D015394:Molecular Structure
D000970:Antineoplastic Agents; D002518:Ceramides