VP-16-induced nucleotide pool changes and poly(ADP-ribose) synthesis: the role of VP-16 in interphase death.
Exposure of human promyelocytic leukemia cell line (HL-60) to VP-16 resulted in accumulation of DNA strand breaks. Concomitantly, intracellular NAD levels fell at 1 h, followed by declines in ATP at 2 h and in GTP, CTP, and UTP at 3 h. Furthermore, marked morphological changes, such as loss of microvilli or bleb formation, appeared at 4 h and cell death by 8-10 h. The addition of an inhibitor of poly(ADP-ribose) polymerase, 3-aminobenzamide (5 mM), theophylline (2 mM), or thymidine (1 mM), prevented these sequential reductions of nucleotide pools and cell death. In fact, the activation of poly(ADP-ribose) synthesis was detectable within a few hours after treatment with VP-16, although it was smaller than that induced by N-methyl-N'-nitro-N-nitrosoguanidine. These results may suggest the possible role of activation of poly(ADP-ribosyl)ation in VP-16-induced nucleotide pool changes and subsequent interphase death.
Tanizawa
A
A
Department of Pediatrics, Kyoto University, Japan.
Kubota
M
M
Hashimoto
H
H
Shimizu
T
T
Takimoto
T
T
Kitoh
T
T
Akiyama
Y
Y
Mikawa
H
H
D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D007399:Interphase / Q000187:drug effects*; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology*; D009702:Nucleoside Diphosphate Sugars / Q000096:biosynthesis*; D009711:Nucleotides / Q000378:metabolism*; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis* / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology; D013936:Thymidine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology
D001549:Benzamides; D009702:Nucleoside Diphosphate Sugars; D009711:Nucleotides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011506:Proteins; C024857:poly(ADP)-ribosylated proteins; D011064:Poly Adenosine Diphosphate Ribose; D005047:Etoposide; C025160:3-aminobenzamide; D013806:Theophylline; D013936:Thymidine