Effects on growth and energy metabolism in untransformed and transformed BALB/c mouse fibroblasts by a novel cytotoxic compound.
A lipid, recently discovered as a contaminant of endotoxin and White-Type polysaccharide preparations from an unidentified isolate of Serratia marcescens, was named DCX for its direct cytotoxic activity. Previously we have shown that DCX is cytotoxic to several transplantable tumors and transformed cell lines in culture at nanomolar concentrations, while normal fibroblasts were significantly more resistant. In this study the selectivity and mechanism of DCX-mediated cytotoxicity was examined more thoroughly with the use of clonally related cell lines. DCX is growth inhibitory but is not cytotoxic to a BALB/c embryonal cell line. Transformation by Simian Virus 40 renders a cloned derivative cell line sensitive to the cytotoxicity of DCX. Treatment of both cell lines with DCX increased 2-deoxyglucose uptake and lactate production, and decreased ATP levels. Electron micrographs show extensive damage to mitochondria in cells treated with DCX. The results indicate that the growth inhibitory activity of DCX in these cells is due to effects on mitochondria resulting in depletion of cellular ATP. The data suggest that the basis for selective cytotoxicity is in how the different cells are able to cope with lower energy levels.
Keler
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Thomas W. Evans Museum and Dental Institute, University of Pennsylvania, Philadelphia 19104.
Smith
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CA
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D000089662:Doublecortin Protein; D004734:Energy Metabolism / Q000187:drug effects*; D005347:Fibroblasts; D007773:Lactates / Q000032:analysis; D008055:Lipids / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012706:Serratia marcescens / Q000378:metabolism
D001427:Bacterial Toxins; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D007773:Lactates; D008055:Lipids; D000255:Adenosine Triphosphate; D003847:Deoxyglucose