Effect of antioxidants on the mitochondrial activity and toxicity of the cancer drug methylglyoxal bis (guanylhydrazone) in yeast and mammalian cells.
Mitochondria of yeast cells were primary targets of methylglyoxal bis (guanylhydrazone) (MGBG) from the following criteria: (1) selective inhibition of growth of cells utilizing a non-fermentable energy source, (2) inhibition of mitochondrial protein synthesis compared with cytosolic protein synthesis and (3) selective mutagenesis of the mitochondrial genome compared with nuclear mutagenesis. Evidence of primary antimitochondrial activity of MGBG in mammalian cells was provided by greater potency of the drug in guinea pig keratinocyte cultures utilizing glutamine as carbon and energy source compared with fermentable glucose. Cell death was used as a measure of drug toxicity in both yeast and mammalian systems. The antioxidants glutathione, vitamin E and vitamin C reversed toxicity and antimitochondrial activity to a large extent implying that toxic free radical metabolites of the drug are of significance in cellular activity of MGBG.
Cheng
L L
LL
Department of Biology, University College London, U.K.
Collier
D C
DC
Wilkie
D
D
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D005947:Glucose; D005973:Glutamine; D005990:Glycerol; D006168:Guinea Pigs; D015603:Keratinocytes / Q000187:drug effects* / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects*; D008935:Mitoguazone / Q000494:pharmacology*; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000648:ultrastructure; D013053:Spectrophotometry
D000975:Antioxidants; D005973:Glutamine; D005947:Glucose; D008935:Mitoguazone; D005990:Glycerol