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Oxidative stress response triggered by the lipid drug edelfosine indicates lipid peroxidation mediates its cytotoxic effect in yeast
Author(s) -
Bitew Teshager,
Zaremberg Vanina
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.691.3
Subject(s) - lipid peroxidation , gpx1 , chemistry , oxidative stress , biochemistry , antioxidant , gpx4 , glutathione , pharmacology , glutathione peroxidase , biology , catalase , enzyme
Edelfosine (1‐O‐octadecyl‐2‐O‐methyl‐rac‐glycero‐3‐phosphocholine) is the prototype of a family of lipid drugs that interferes with cellular membrane function and selectively induces apoptosis in tumor cells. It has been difficult to further optimize its efficacy as its cellular target(s) has yet to be elucidated. Previously, we have validated S. cerevisiae as model system to study the biochemistry and mode of action of Edelfosine. In this study, we have found that microM concentrations of the antioxidant Vitamin E (alpha‐tocopherol) protected yeast cells from Edelfosine cytotoxicity. We have assessed the possibility of Vitamin E correcting the membrane curvature introduced by Edelfosine. Cells were then challenged with a methylated Vit E that has lost its antioxidant properties but could still be inserted into membranes. This compound could not protect cells from Edelfosine, indicating lipid peroxidation mediates its cytotoxic effect. Furthermore, a genetic approach using strains lacking genes known to protect yeast from oxidative stress identified a small set of mutants lacking phospholipid hydroperoxide glutathione peroxidases (GPX1, GPX2 and GPX3) and the two master transcription factors, YAP1 and SKN7, required for oxidative stress tolerance, as hypersensitive to the drug. Altogether these results strongly support lipid peroxidation mediates Edelfosine effect.