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A more recent version of this article appeared on May 1, 2004

Papers In Press, published online ahead of print February 16, 2004
J. Lipid Res., doi:10.1194/jlr.M300486-JLR200
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Submitted on November 25, 2003
Revised on January 29, 2004
Accepted on February 5, 2004

Oligonucleotides blocking glucosylceramide synthase expression selectively reverse drug resistance in cancer cells

Yong-Yu Liu, Tie Yan Han, Jing Yuan Yu, Arie Bitterman, Ahn Le, Armando E. Giuliano, and Myles C. Cabot

Department of Experimental Therapeutics, John Wayne Cancer Institute, Santa Monica, CA 90404

Corresponding Author: yong{at}jwci.org

High glucosylceramide synthase (GCS) activity is one factor contributing to multidrug resistance (MDR) in breast cancer. Enforced GCS overexpression has been shown to disrupt ceramide-induced apoptosis and confer resistance to doxorubicin. To examine whether GCS is a target for cancer therapy, we have designed and tested the effects of antisense oligodeoxyribonucleotides (ODN) to GCS on gene expression and chemosensitivity in MDR cancer cells. Here we demonstrate that antisense GCS ODN-7 (asGCS ODN-7) blocked cellular GCS expression and selectively increased the cytotoxicity of anticancer agents. Pretreatment with asGCS ODN-7 increased doxorubicin sensitivity by 17-fold in MCF-7-AdrR (doxorubicin resistant) breast cancer cells, and by 10-fold in A2780-AD (doxorubicin resistant) ovarian cancer cells. In MCF-7 drug-sensitive breast cancer cells, asGCS ODN-7 only increased doxorubicin sensitivity 3-fold, and did not influence doxorubicin cytotoxicity in normal human mammary epithelial cells. asGCS ODN-7 was shown to be more efficient in reversing drug resistance than either the GCS chemical inhibitor, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, PDMP, or P-glycoprotein blocking agents, verapamil and cyclosporin A. Experiments defining drug transport and lipid metabolism parameters showed that asGCS ODN-7 overcomes drug resistance mainly by enhancing drug uptake and ceramide-induced apoptosis. This study demonstrates that a 20-mer asGCS oligonucleotide effectively reverses MDR in human cancer cells.


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