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Mitochondrial-derived ROS in edelfosine-induced apoptosis in yeasts and tumor cells
Hui Zhang1, Consuelo Gajate, Li-Ping Yu
1Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
Aim:
To investigate whether a similar process mediates cytotoxicity of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3, edelfosine) in both yeasts and human tumor cells.
Methods:
A modified version of a previously described assay for the intracellular conversion of nitro blue tetrazolium to formazan by superoxide anion was used to measure the generation of reactive oxygen species (ROS). Apoptotic yeast cells were detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. DNA fragmentation and the generation of ROS were measured by cytofluorimetric analysis in Jurkat cells.
Results:
Edelfosine induced apoptosis in Saccharomyces cerevisiae, as assessed by TUNEL assay. Meanwhile, edelfosine induced a time- and concentration-dependent generation of ROS in yeasts. Rotenone, an inhibitor of the mitochondrial electron transport chain, prevented ROS generation and apoptosis in response to edelfosine in S cerevisiae. alpha-Tocopherol abrogated the edelfosine-induced generation of intracellular ROS and apoptosis. Edelfosine also induced an increase of ROS in human leukemic cells that preceded apoptosis. The overexpression of Bcl-2 by gene transfer abrogated both ROS generation and apoptosis induced by edelfosine in leukemic cells. Changes in the relative mitochondrial membrane potential were detected in both yeasts and Jurkat cells.
Conclusion:
These results indicate that edelfosine induces apoptosis in yeasts in addition to human tumor cells, and this apoptotic process involves mitochondria, likely through mitochondrial-derived ROS. These data also suggest that yeasts can be used as a suitable cell model in elucidating the antitumor mechanism of action of edelfosine.
Insights
Edelfosine induces apoptosis in yeast and human tumor cells by generating reactive oxygen species (ROS) from mitochondria. This suggests yeast can model edelfosine
Area of Science:
- Cell Biology
- Biochemistry
- Pharmacology
Background:
- 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3, edelfosine) is an alkylphosphocholine with demonstrated antitumor activity.
- The precise mechanisms underlying edelfosine's cytotoxicity, particularly its role in inducing apoptosis, require further elucidation.
Purpose of the Study:
- To investigate if the cytotoxic mechanism of edelfosine in human tumor cells is conserved in yeast.
- To explore the role of reactive oxygen species (ROS) and mitochondrial function in edelfosine-induced apoptosis.
Main Methods:
- Assessed ROS generation using a modified nitro blue tetrazolium assay.
- Detected apoptotic yeast cells via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay.
- Utilized cytofluorimetric analysis for DNA fragmentation and ROS measurement in Jurkat cells.
Main Results:
- Edelfosine induced apoptosis and ROS generation in Saccharomyces cerevisiae, inhibited by rotenone and alpha-tocopherol.
- Edelfosine increased ROS in human leukemic cells prior to apoptosis; Bcl-2 overexpression abrogated these effects.
- Mitochondrial membrane potential changes were observed in both yeast and Jurkat cells.
Conclusions:
- Edelfosine induces apoptosis in yeast and human tumor cells through a mitochondrion-dependent pathway involving ROS.
- Yeast serves as a viable model for studying the antitumor mechanisms of edelfosine.
