PDMP sensitizes neuroblastoma to paclitaxel by inducing aberrant cell cycle progression leading to hyperploidy.
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.
Dijkhuis
Anne-Jan
AJ
Department of Cell Biology, Section Membrane Cell Biology, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands.
Klappe
Karin
K
Jacobs
Susan
S
Kroesen
Bart-Jan
BJ
Kamps
Willem
W
Sietsma
Hannie
H
Kok
Jan Willem
JW
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002518:Ceramides / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D009025:Morpholines / Q000627:therapeutic use*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use*; D011123:Polyploidy; D013107:Sphingolipids / Q000096:biosynthesis
D000970:Antineoplastic Agents; D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D009025:Morpholines; D013107:Sphingolipids; C033110:RV 538; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2; D017239:Paclitaxel; C001996:thermozymocidin