Ceramide toxicity and metabolism differ in wild-type and multidrug-resistant cancer cells.

  • Authors:
    • A Lucci
    • A E Giuliano
    • T Y Han
    • T Dinur
    • Y Y Liu
    • A Senchenkov
    • M C Cabot
  • View Affiliations

  • Published online on: September 1, 1999     https://doi.org/10.3892/ijo.15.3.535
  • Pages: 535-575
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Abstract

Previously we demonstrated that multidrug-resistant (MDR) cancer cells have elevated levels of a glycosylated form of ceramide, glucosylceramide. Here we compared ceramide metabolism and ceramide toxicity in MCF-7 and in adriamycin-resistant (MCF-7-AdrR) human breast cancer cells. MCF-7-AdrR cells were resistant to C6-ceramide (1-10 microM); however, in MCF-7 cells treated with C6-ceramide, viability dropped sharply. Ceramide, when supplemented, was not metabolized by MCF-7 cells. In contrast, ceramide was efficiently converted to glucosylceramide by MCF-7-AdrR cells. Analysis of extracellular [3H]ceramide in radiolabeled cells showed that MCF-7-AdrR cells do not have an enhanced capacity to efflux ceramide compared with MCF-7 cells. Triphenylethylene anti-estrogens, known modulators of drug resistance, were effective inhibitors of ceramide conversion to glucosylceramide, suggesting that blocking ceramide metabolism plays a role in chemosensitization. The anti-progestine, RU486, also blocked glucosylceramide synthesis in cells; however, LY117018, a raloxifene analog, was without influence. We propose that an enhanced capacity to glycosylate ceramide as evidenced in MCF-7-AdrR cells, is a molecular determinant of drug resistance, particularly as regards resistance to ceramide-enhancing agents such as anthracyclines, ionizing radiation, and tumor necrosis factor-alpha.

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September 1999
Volume 15 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Lucci, A., Giuliano, A., Han, T., Dinur, T., Liu, Y., Senchenkov, A., & Cabot, M. (1999). Ceramide toxicity and metabolism differ in wild-type and multidrug-resistant cancer cells.. International Journal of Oncology, 15, 535-575. https://doi.org/10.3892/ijo.15.3.535
MLA
Lucci, A., Giuliano, A., Han, T., Dinur, T., Liu, Y., Senchenkov, A., Cabot, M."Ceramide toxicity and metabolism differ in wild-type and multidrug-resistant cancer cells.". International Journal of Oncology 15.3 (1999): 535-575.
Chicago
Lucci, A., Giuliano, A., Han, T., Dinur, T., Liu, Y., Senchenkov, A., Cabot, M."Ceramide toxicity and metabolism differ in wild-type and multidrug-resistant cancer cells.". International Journal of Oncology 15, no. 3 (1999): 535-575. https://doi.org/10.3892/ijo.15.3.535