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¹ Department of Cell Biology, Section of Membrane Cell Biology, ² Departments of Pediatric Oncology and Hematology, Beatrix Children's Hospital, and ³ Pathology and Laboratory Medicine, University Medical Center Groningen, Groningen, the Netherlands

Requests for reprints: Jan Willem Kok, Department of Cell Biology, Section Membrane Cell Biology, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands. Phone: 31-50-3632725; Fax: 31-50-3632728. E-mail: j.w.kok{at}med.umcg.nl

The sphingolipid ceramide has been recognized as an important mediator in the apoptotic machinery, and its efficient conversion to glucosylceramide has been associated with multidrug resistance. Therefore, inhibitors of glucosylceramide synthase are explored as tools for treatment of cancer. In this study, we used D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol to sensitize Neuro-2a murine neuroblastoma cells to the microtubule-stabilizing agent paclitaxel. This treatment resulted in a synergistic inhibition of viable cell number increase, which was based on a novel mechanism: (a) After a transient mitotic arrest, cells proceeded through an aberrant cell cycle resulting in hyperploidy. Apoptosis also occurred but to a very limited extent. (b) Hyperploidy was not abrogated by blocking de novo sphingolipid biosynthesis using ISP-1, ruling out involvement of ceramide as a mediator. (c) Cyclin-dependent kinase 1 and 2 activities were synergistically decreased on treatment. In conclusion, instead of inducing apoptosis through ceramide accumulation, D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol by itself affects cell cycle–related proteins in paclitaxel-arrested Neuro-2a cells resulting in aberrant cell cycle progression leading to hyperploidy. [Mol Cancer Ther 2006;5(3):593–601]

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Received 11/ 4/05; revised 12/21/05; accepted 1/12/06.