1. The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function.
- Author
-
Chai L, McLaren RP, Byrne A, Chuang WL, Huang Y, Dufault MR, Pacheco J, Madhiwalla S, Zhang X, Zhang M, Teicher BA, Carter K, Cheng SH, Leonard JP, Xiang Y, Vasconcelles M, Goldberg MA, Copeland DP, Klinger KW, Lillie J, Madden SL, and Jiang YA
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis drug effects, Cell Proliferation drug effects, Dioxanes administration & dosage, Doxorubicin administration & dosage, Doxorubicin pharmacology, Drug Evaluation, Preclinical, Drug Resistance, Neoplasm genetics, Drug Synergism, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacology, Gene Expression Regulation, Neoplastic drug effects, Hep G2 Cells, Humans, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, Pyrrolidines administration & dosage, RNA, Small Interfering pharmacology, Tumor Cells, Cultured, ATP Binding Cassette Transporter, Subfamily B, Member 1 physiology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Dioxanes pharmacology, Drug Resistance, Neoplasm drug effects, Glucosyltransferases antagonists & inhibitors, Neoplasms drug therapy, Pyrrolidines pharmacology
- 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.
- Published
- 2011
- Full Text
- View/download PDF