1-phenyl-2-decanoylamino-3-morpholino-1-propanol chemosensitizes neuroblastoma cells for taxol and vincristine

In this study, we show that an inhibitor of glycosphingolipid biosynthesis, D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), increas es the chemosensitivity of neuroblastoma tumor cells for Taxol and vincrist ine. At noneffective low doses of Taxol or vincristine, the addition of a n oneffective dose of PDMP resulted in 70% cytotoxicity, indicating synergy. Such an effect was not observed for etoposide (VP16), PDMP caused an early (6 h) increase in ceramide (Cer) levels, but the excess Cer was metabolical ly removed in the long-term (96 h), However, upon incubation with PDMP in c ombination with Taxol, but not with etoposide, Cer levels remained elevated at 96 h, These results suggest that neuroblastoma cells are normally able to metabolically remove excess Cer, but lose this capacity upon exposure to microtubule modulating anticancer agents (Taxol or vincristine), In additi on, PDMP treatment resulted in a decreased efflux of [C-14]Taxol and [H-3]v incristine from neuroblastoma cells, similar to treatment with PSC833 or MK 571, suggesting an effect of PDMP on the transporter proteins P-glycoprotei n and/or multidrug resistance protein. PDMP did not further reduce [C-14]Ta xol or [H-3]vincristine efflux in PSC833-treated cells, although it did fur ther diminish cell survival under these conditions, We conclude that a comb ined administration of nontoxic concentrations of PDMP and either Taxol or vincristine results in highly sensitized neuroblastoma cells. This appears to involve a sustained elevation of Cer levels, possibly in concert with in creased drug accumulation.