Glucocorticoid-induced cell death and poly[adenosine diphosphate(ADP)-ribosyl]ation: increased toxicity of dexamethasone on mouse S49.1 lymphoma cells with the poly(ADP-ribosyl)ation inhibitor benzamide.
Treatment of S49.1 mouse lymphoma cells with the synthetic glucocorticoid dexamethasone resulted in a delayed cell death. During the 24-h latency period, DNA, RNA, and protein synthesis fell to about 50%, 60%, and 30% of control values, respectively, without a change in ATP levels, the latter suggesting cellular integrity. The onset of cellular suicide was characterized by the occurrence of DNA strand breaks, finally leading to the total digestion of internucleosomal DNA. Concomitant with the appearance of DNA fragmentation, poly(ADP-ribosyl)ation was activated, a process probably involved in DNA repair. Activation of poly(ADP-ribose)synthetase was paralleled by a fall in the level of the substrate NAD. An antagonistic role of poly(ADP-ribosyl)ation in glucocorticoid-induced cell death was suggested by the observation that low concentrations of the potent poly(ADP-ribose)synthetase inhibitor benzamide enhanced the toxicity of dexamethasone several-fold and shortened the interval between steroid addition and the onset of cell death. In addition, the fall in NAD was prevented by benzamide. The antagonistic function of poly(ADP-ribosyl)ation in glucocorticoid-induced cell death is, therefore, comparable to the role of the poly(ADP-ribose)synthetase in cells treated with alkylating agents, suggesting involvement of a DNA repair phenomenon in opposition to the mechanism of glucocorticoid-induced cell death.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects; D003907:Dexamethasone / Q000633:toxicity*; D004357:Drug Synergism; D008223:Lymphoma / Q000378:metabolism*; D051379:Mice; D009243:NAD / Q000378:metabolism; D009702:Nucleoside Diphosphate Sugars / Q000378:metabolism*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis
D001549:Benzamides; D009702:Nucleoside Diphosphate Sugars; D009243:NAD; D011064:Poly Adenosine Diphosphate Ribose; D012313:RNA; C037689:benzamide; D003907:Dexamethasone; D000255:Adenosine Triphosphate