1-phenyl-2-decanoylamino-3-morpholino-1-propanol chemosensitizes neuroblastoma cells for taxol and vincristine.
In this study, we show that an inhibitor of glycosphin-golipid biosynthesis, D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), increases the chemosensitivity of neuroblastoma tumor cells for Taxol and vincristine. At noneffective low doses of Taxol or vincristine, the addition of a noneffective 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 metabolically removed in the long-term (96 h). However, upon incubation with PDMP in combination 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 addition, PDMP treatment resulted in a decreased efflux of [14C]Taxol and [3H]vincristine from neuroblastoma cells, similar to treatment with PSC833 or MK571, suggesting an effect of PDMP on the transporter proteins P-glycoprotein and/or multidrug resistance protein. PDMP did not further reduce [14C]Taxol or [3H]vincristine efflux in PSC833-treated cells, although it did further diminish cell survival under these conditions. We conclude that a combined 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 increased drug accumulation.
Sietsma
H
H
Groningen Utrecht Institute for Drug Exploration, Department of Pediatric Oncology, Beatrix Children's Hospital, The Netherlands.
Veldman
R J
RJ
Kolk
D
D
Ausema
B
B
Nijhof
W
W
Kamps
W
W
Vellenga
E
E
Kok
J W
JW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009447:Neuroblastoma / Q000473:pathology / Q000517:prevention & control*; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002518:Ceramides; D003524:Cyclosporins; D004791:Enzyme Inhibitors; D009025:Morpholines; D014750:Vincristine; D005047:Etoposide; C033110:RV 538; D005964:Glucosyltransferases; D017239:Paclitaxel; C070272:valspodar