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Retinoic acid reduces the cytotoxicity of cyclopentenyl cytosine in neuroblastoma cells
Author(s) -
Bierau Jörgen,
van Gennip Albert H,
Leen René,
Caron Huib N,
van Kuilenburg André B.P
Publication year - 2002
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(02)03234-9
Subject(s) - retinoic acid , cytidine , cytosine , neuroblastoma , chemistry , uridine , nucleotide salvage , apoptosis , biochemistry , cytotoxicity , tretinoin , microbiology and biotechnology , biology , enzyme , cell culture , in vitro , rna , dna , gene , nucleotide , genetics
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.