Can P-glycoprotein influence the bioavailability of iminosugar-based glucosylceramide synthase inhibitors?

Norris-Cervetto, Edward; Butters, Terry D.; Martin, Catherine A.; Modok, Szabolcs; Dwek, Raymond A.; Callaghan, Richard

doi:10.1016/j.ejphar.2005.11.038

Cited by 4 publications

(2 citation statements)

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“…An increase in intracellular calcein fluorescence was also detected in the cells exposed to Genz-123346, indicating that Genz-123346 is a P-gp/MRP substrate. In contrast, C4DGJ and 5-FU did not affect intracellular calcein fluorescence, consistent with previous reports that these compounds are not P-gp substrates (25,35,37).…”

Section: The Ceramide-based Inhibitors Of Gcs (Pdmp and Genz-123346) supporting

confidence: 80%

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

Madden¹

2011

Int J Oncol

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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 nontoxic 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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Section: The Ceramide-based Inhibitors Of Gcs (Pdmp and Genz-123346) supporting

confidence: 80%

“…4C). Nevertheless, cellular drug accumulation in P-gp over-expressing NCI/ADR-RES cells treated with PDMP was not observed in previous studies (22,37). Therefore, the modulation of P-gp function by PDMP seems, at the very least, to be cell line-dependent.…”

Section: Discussionmentioning

confidence: 51%