Retinoic acid reduces the cytotoxicity of cyclopentenyl cytosine in neuroblastoma cells.
In this paper, it is demonstrated that all-trans, 9-cis and 13-cis retinoic acid (RA) decreased the sensitivity of SK-N-BE(2)c neuroblastoma cells towards the chemotherapeutic agent cyclopentenyl cytosine (CPEC), a potent inhibitor of cytosine-5'-triphosphate synthetase. Retinoic acid attenuated CPEC-induced apoptosis as reflected by a decreased caspase-3 induction. Retinoic acid decreased the accumulation of CPEC, whereas the salvage of cytidine was strongly increased. Metabolic labeling studies using [(3)H]uridine showed a strongly decreased biosynthesis of CTP via CTP synthetase. Retinoic acid likely confers resistance of neuroblastoma cells to CPEC in part by slowing down proliferation, and in part by shifting the synthesis of CTP towards the salvage of cytidine, thereby bypassing CTP synthetase.
Bierau
Jörgen
J
Academic Medical Center, University of Amsterdam, Department of Clinical Chemistry and Emma Children's Hospital, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands.
van Gennip
Albert H
AH
Leen
René
R
Caron
Huib N
HN
van Kuilenburg
André B P
AB
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003570:Cytidine Triphosphate / Q000096:biosynthesis; D004347:Drug Interactions; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011122:Polyphosphates / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011122:Polyphosphates; D014212:Tretinoin; D003562:Cytidine; D003570:Cytidine Triphosphate; C045911:cyclopentenyl cytosine; C005692:triphosphoric acid