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C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth

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Abstract

The sphingolipid ceramide is known to play a central role in chemo- and radiation-induced cell death. Acid ceramidase (AC) hydrolyzes ceramide, and thus reduces intracellular levels of this proapoptotic lipid. The role of AC as a putative anticancer target is supported by reports of upregulation in prostate cancer and in some breast tumors. In this study, we determined whether the introduction of an AC inhibitor would enhance the apoptosis-inducing effects of C6-ceramide (C6-cer) in breast cancer cells. Cultured breast cancer cells were treated with DM102 [(2R,3Z)-N-(1-hydroxyoctadec-3-en-2-yl)pivalamide, C6-cer, or the combination. Cell viability and cytotoxic synergy were assessed. Activation of apoptotic pathways, generation of reactive oxygen species, and mitochondrial transmembrane potential were determined. DM102 was a more effective AC inhibitor than N-oleoylethanolamine (NOE) and (1R,2R)-2-N-(tetradecanoylamino)-1-(4′-nitrophenyl)-1,3-propandiol (B-13) in MDA-MB-231, MCF-7, and BT-474 cells. As single agents, C6-cer (IC50 5–10 μM) and DM102 (IC50 20 μM) were only moderately cytotoxic in MDA-MB-231, MCF-7, and SK-BR-3 cells. Co-administration, however, produced synergistic decreases in viability (combination index <0.5) in all cell lines. Apoptosis was confirmed in MDA-MB-231 cells by detection of caspase 3 cleavage and a >3-fold increase in caspase 3/7 activation, PARP cleavage, and a >70% increase in Annexin-V positive cells. C6-cer/DM102 increased ROS levels 4-fold in MDA-MB-231 cells, shifted the ratio of Bax:Bcl-2 to >9-fold that of control cells, and resulted in mitochondrial membrane depolarization. DM102 also increased the synthesis of 3H-palmitate-labeled long-chain ceramides by 2-fold when C6-cer was present. These data support the effectiveness of targeting AC in combination with exogenous short-chain ceramide as an anticancer strategy, and warrant continued investigation into the utility of the C6-cer/DM102 drug duo in human breast cancer.

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Acknowledgments

This research was supported by the Association for Breast and Prostate Cancer Studies (Los Angeles), the Fashion Footwear Association of New York Charitable Foundation (New York, NY), National Institute of General Medical Sciences (grant no. GM77391), and the Spanish Ministerio de Ciencia e Innovación (Grant no. SAF2008-00706). We thank Matthew Bush for compiling the typescript and creating the figures.

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Authors and Affiliations

  1. Department of Experimental Therapeutics, John Wayne Cancer Institute, Santa Monica, CA, USA

    Margaret Flowers & Myles C. Cabot

  2. Departament de Química Biomèdica, Institut de Química Avançada de Catalunya, Spanish National Research Council (Consejo Superior de Investigaciones Científicas, CSIC), Research Unit on Bioactive Molecules, Barcelona, Spain

    Gemma Fabriás, Antonio Delgado, Josefina Casas & Jose Luis Abad

  3. Unitat de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain

    Antonio Delgado

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  1. Margaret Flowers
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Correspondence to Myles C. Cabot.

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Flowers, M., Fabriás, G., Delgado, A. et al. C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth. Breast Cancer Res Treat 133, 447–458 (2012). https://doi.org/10.1007/s10549-011-1768-8

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