Thymidylate synthase inhibition triggers glucose-dependent apoptosis in p53-negative leukemic cells.
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.
Muñoz-Pinedo
Cristina
C
Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Científicas, calle Ventanilla 11, 18001 Granada, Spain. cmunoz@liai.org
Robledo
Gema
G
López-Rivas
Abelardo
A
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005467:Floxuridine / Q000494:pharmacology; D016158:Genes, p53; D005947:Glucose / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species; D013936:Thymidine / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D020298:U937 Cells; D014529:Uridine / Q000494:pharmacology; D019014:fas Receptor / Q000096:biosynthesis
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D019014:fas Receptor; D005467:Floxuridine; D045304:Cytochromes c; D013940:Thymidylate Synthase; D020169:Caspases; D005978:Glutathione; D005947:Glucose; D013936:Thymidine; D014529:Uridine