Cycloheximide protection against actinomycin D cytotoxicity.
Pretreatment plus concomitant treatment with 10 micrograms/ml cycloheximide protected Chinese hamster ovary cells and Swiss 3T3 cells against the cytotoxicity of actinomycin D. The cycloheximide treatment reduced the intracellular concentration of actinomycin D by reducing the level of actinomycin D bound to the acid precipitable fraction of the cell. Levels of unbound actinomycin D were unaffected by cycloheximide, indicating that the plasma membrane permeability to AD was not reduced. Actinomycin D inhibited total transcription but did not reduce cytoplasmic levels of rRNA nor of most tested mRNA; however, cytoplasmic levels of c-myc mRNA were reduced below detectability. Cycloheximide treatment further inhibited total transcription and had no effect on cytoplasmic levels of rRNA nor of most tested mRNA. Cytoplasmic levels of c-myc were elevated by cycloheximide and remained so even in the presence of actinomycin D. These data suggested that a reduction in cytoplasmic levels of short lived, essential mRNA, such as c-myc mRNA, was one lethal lesion of actinomycin D. Furthermore, cycloheximide's protection may result, in part, from its ability to stabilize and/or elevate cytoplasmic levels of these mRNA, thus counteracting their depletion by actinomycin D. Protection may also result from the cycloheximide-induced reduction of actinomycin D bound to the acid precipitable fraction of the cells.
D000818:Animals; D015152:Blotting, Northern; D016466:CHO Cells / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003513:Cycloheximide / Q000494:pharmacology*; D003609:Dactinomycin / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D013696:Temperature; D014529:Uridine / Q000493:pharmacokinetics
D003609:Dactinomycin; D012313:RNA; D003513:Cycloheximide; D014529:Uridine