2-3-n-octanoylsphingosine and Breast-Neoplasms

The ceramide-sphingosine-1-phosphate rheostat is a promising therapeutic target. Here, the novel ceramide analog (S)-2-(benzylideneamino)-3-hydroxy-N-tetrade-cylpropanamide is shown to block proliferation and enhance the efficacy of the clinical chemotherapeutics, etoposide and doxorubicin. These results demonstrate the therapeutic potential of this compound in treating both endocrine resistant and chemoresistant breast cancer.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Ceramides; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Etoposide; Female; Humans; Ki-67 Antigen; Lysophospholipids; Sphingosine; Stereoisomerism; Structure-Activity Relationship

A group of novel L-serinamides, substituted (S)-2-(benzylideneamino)-3-hydroxy-N-tetradecylpropanamides (3a-o) and substituted (S)-2-(benzylamino)-3-hydroxy-N-tetradecyl propanamides (4c, 4i, 4l, and 4o), were synthesized as potential anti-tumor lead compounds. In vitro cell viability assay results indicate treatment with 3a-o compounds resulted in significant inhibition of cell viability in the chemoresistant breast cancer cell line, MCF-7TN-R. Compounds 3i and 3l, both ortho-substituted analogs, show the greatest efficacy with IC50 values of 10.3 microM and 12.5 microM, respectively. The SAR analysis indicate that the imine functional group of 3a-o is critical for the cellular anti-viability effect, and the partial atomic charge (PAC) value of imine C atom is a valuable structural parameter for predicting the activity of these ceramide analogs.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Survival; Ceramides; Drug Resistance, Neoplasm; Female; Humans; Inhibitory Concentration 50; Structure-Activity Relationship

Resistance to chemotherapy and endocrine therapy is a major cause of breast cancer treatment failure. We have synthesized six novel analogues using C8-ceramide as the lead analogue and studied their effect on hormone therapy resistant (MDA-MB-231) and chemoresistant (MCF-7TN-R) breast cancer cells. Pharmacologic intervention using these ceramide analogues inhibited clonogenic survival and induced apoptosis, with one analogue being more effective than C8-ceramide. Our results show ceramide-based therapy has therapeutic potential in treating drug resistant breast cancer.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Ceramides; Drug Design; Drug Resistance, Neoplasm; Hormones; Humans; Inhibitory Concentration 50; Lysophospholipids; Sphingosine