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 resistance 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis / drug effects
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Cell Proliferation / drug effects
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Dioxanes / administration & dosage
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Dioxanes / pharmacology*
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Doxorubicin / administration & dosage
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Doxorubicin / pharmacology
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Drug Evaluation, Preclinical
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Drug Synergism
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Glucosyltransferases / antagonists & inhibitors*
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Hep G2 Cells
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Humans
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Neoplasms / drug therapy*
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology
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Pyrrolidines / administration & dosage
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Pyrrolidines / pharmacology*
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RNA, Small Interfering / pharmacology
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Tumor Cells, Cultured
Substances
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(2-(2',3'-dihydrobenzo(1,4)dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethylethyl)nonanoic acid amide
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Dioxanes
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Enzyme Inhibitors
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Pyrrolidines
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RNA, Small Interfering
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Doxorubicin
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Glucosyltransferases
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ceramide glucosyltransferase