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Journal of Lipid Research, Vol. 45, 933-940, May 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

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

Yong-Yu Liu^1,*, Tie Yan Han^*, Jing Yuan Yu^*, Arie Bitterman, Ahn Le^*, Armando E. Giuliano^* and Myles C. Cabot^1,*

^* John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA
Department of Surgery A, Carmel Medical Center, Haifa, Israel

¹ To whom correspondence should be addressed. e-mail: yong{at}jwci.org (Y-Y.L.); cabot{at}jwci.org (M.C.C.)

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 to confer resistance to doxorubicin. To examine whether GCS is a target for cancer therapy, we have designed and tested the effects of antisense oligodeoxyribonucleotides (ODNs) to GCS on gene expression and chemosensitivity in multidrug-resistant cancer cells. Here, we demonstrate that antisense GCS (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 by 3-fold, and it 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 or the 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.

Abbreviations: asGCS, antisense glucosylceramide synthase; GCS, glucosylceramide synthase (ceramide:UDP-glucosyltransferase); HMEC, human mammary epithelial cells; NB-DNJ, N-butyldeoxynojirimycin; OD, optical density; ODN, oligodeoxyribonucleotide; PDMP, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol

Supplementary key words ceramide • antisense oligonucleotides • apoptosis • chemotherapy • breast cancer • doxorubicin • drug uptake • D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol

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