The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function

  • Authors:
    • Lilly Chai
    • Rajashree P. McLaren
    • Ann Byrne
    • Wei-Lien Chuang
    • Yinyin Huang
    • Michael R. Dufault
    • Joshua Pacheco
    • Shruti Madhiwalla
    • Xiaokui Zhang
    • Mindy Zhang
    • Beverly A. Teicher
    • Kara Carter
    • Seng H. Cheng
    • John P. Leonard
    • Yibin Xiang
    • Michael Vasconcelles
    • Mark A. Goldberg
    • Diane P. Copeland
    • Katherine W. Klinger
    • James Lillie
    • Stephen L. Madden
    • Yide A. Jiang
  • View Affiliations

  • Published online on: December 24, 2010     https://doi.org/10.3892/ijo.2010.888
  • Pages: 701-711
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Abstract

Glucosylceramide synthase (GCS) is a key enzyme engaged in the biosynthesis of glycosphingolipids and in regulating ceramide metabolism. Studies exploring alterations in GCS activity suggest that the glycolase may have a role in chemosensitizing tumor cells to various cancer drugs. The chemosensitizing effect of inhibitors of GCS (e.g. PDMP and selected analogues) has been observed with a variety of tumor cells leading to the proposal that the sensitizing activity of GCS inhibitors is primarily through increases in intracellular ceramide leading to induction of apoptosis. The current study examined the chemosensitizing activity of the novel GCS inhibitor, Genz-123346 in cell culture. Exposure of cells to Genz-123346 and to other GCS inhibitors at non-toxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents. This activity was unrelated to lowering intracellular glycosphingolipid levels. Genz-123346 and a few other GCS inhibitors are substrates for multi-drug reisistance efflux pumps such as P-gp (ABCB1, gP-170). In cell lines selected to over-express P-gp or which endogenously express P-gp, chemosensitization by Genz-123346 was primarily due to the effects on P-gp function. RNA interference studies using siRNA or shRNA confirmed that lowering GCS expression in tumor cells did not affect their responsiveness to commonly used cytotoxic drugs.

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March 2011
Volume 38 Issue 3

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Spandidos Publications style
Chai L, McLaren RP, Byrne A, Chuang W, Huang Y, Dufault MR, Pacheco J, Madhiwalla S, Zhang X, Zhang M, Zhang M, et al: The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function. Int J Oncol 38: 701-711, 2011
APA
Chai, L., McLaren, R.P., Byrne, A., Chuang, W., Huang, Y., Dufault, M.R. ... Jiang, Y.A. (2011). The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function. International Journal of Oncology, 38, 701-711. https://doi.org/10.3892/ijo.2010.888
MLA
Chai, L., McLaren, R. P., Byrne, A., Chuang, W., Huang, Y., Dufault, M. R., Pacheco, J., Madhiwalla, S., Zhang, X., Zhang, M., Teicher, B. A., Carter, K., Cheng, S. H., Leonard, J. P., Xiang, Y., Vasconcelles, M., Goldberg, M. A., Copeland, D. P., Klinger, K. W., Lillie, J., Madden, S. L., Jiang, Y. A."The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function". International Journal of Oncology 38.3 (2011): 701-711.
Chicago
Chai, L., McLaren, R. P., Byrne, A., Chuang, W., Huang, Y., Dufault, M. R., Pacheco, J., Madhiwalla, S., Zhang, X., Zhang, M., Teicher, B. A., Carter, K., Cheng, S. H., Leonard, J. P., Xiang, Y., Vasconcelles, M., Goldberg, M. A., Copeland, D. P., Klinger, K. W., Lillie, J., Madden, S. L., Jiang, Y. A."The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function". International Journal of Oncology 38, no. 3 (2011): 701-711. https://doi.org/10.3892/ijo.2010.888