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Thymidylate synthase inhibition triggers glucose‐dependent apoptosis in p53‐negative leukemic cells
Author(s) -
Muñoz-Pinedo Cristina,
Robledo Gema,
López-Rivas Abelardo
Publication year - 2004
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/j.febslet.2004.06.044
Subject(s) - thymidylate synthase , apoptosis , cytochrome c , k562 cells , biology , chemistry , mitochondrion , deoxyuridine , microbiology and biotechnology , atp synthase , biochemistry , dna , enzyme , fluorouracil , genetics , chemotherapy
Chemotherapeutic drugs that inhibit the synthesis of DNA precursor thymidine triphosphate cause apoptosis, although the mechanism underlying this process remains rather unknown. Here, we describe thymineless death of human myeloid leukemia U937 cells treated with the thymidylate‐synthase inhibitor 5 ′ ‐fluoro‐2 ′ ‐deoxyuridine (FUdR). This apoptotic process was shown to be independent of p53, reactive oxygen species generation and CD95 activation. Caspases were activated downstream of cytochrome c but upstream of mitochondrial depolarization. Furthermore, FUdR‐induced apoptosis required the presence of glucose in the culture medium at a step upstream of the release of cytochrome c from mitochondria.