Abstract A32: Novel ceramide analogs induce apoptosis in chemoresistant breast cancer.

Abstract

Abstract Ceramide, a central molecule in sphingolipid metabolism, has been shown to mediate cell death by both apoptotic and non-apoptotic pathways. However, the use of endogenous ceramides as a pharmacological intervention is limited by the naturally hydrophobic nature of the ceramide molecule, which prevents efficient penetration of the cellular membrane. One novel approach is to synthesize ceramide analogs with a greater efficacy and specificity than endogenous ceramides. Our laboratory has previously shown that ceramide analogs have therapeutic potential in the treatment of chemo-sensitive and -resistant breast cancer. In this study, the effect of 5 novel ceramide analogs (designated 401–406) on cellular viability and clonogenic survival was examined in the chemosensitive MCF-7, endocrine-resistant MDA-MB-231, and chemoresistant MCF-7TN-R breast cancer cell lines, as well as the Human Embryonic Kidney (HEK) cell line. In the viability assay, analogs 401 and 406 showed the greatest efficacy in the MCF7-TNR cell line, with IC50 values of 4.0 μM and 4.2 μM in metastatic MCF-7TN-R cells. In the clonogenic survival assay, analogs 401 and 406 were again the most effective in the MCF7-TNR cell line with IC50 values of 1.9 and 1.8 respectively. Additionally, Analog 406 showed a 3.8 fold increase over control in the induction of apoptosis (p<0.05), and demonstrated a 3.4-fold increase in caspase-9 activity (p<0.05). Because ceramide has been shown to be involved in tumor sensitivity to apoptosis and chemoresistance, we suggest that development of ceramide analogs with increased antitumor activity represents a potential new class of chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A32.