Abstract
Lipid rafts and mitochondria are promising targets in cancer therapy. The synthetic antitumor alkyl-lysophospholipid analog edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) has been reported to target lipid rafts. Here, we have found that edelfosine induced loss of mitochondrial membrane potential and apoptosis in human cervical carcinoma HeLa cells, both responses being abrogated by Bcl-xL overexpression. We synthesized a number of new fluorescent edelfosine analogs, which preserved the proapoptotic activity of the parent drug, and colocalized with mitochondria in HeLa cells. Edelfosine induced swelling in isolated mitochondria, indicating an increase in mitochondrial membrane permeability. This mitochondrial swelling was independent of reactive oxygen species generation. A structurally related inactive analog was unable to promote mitochondrial swelling, highlighting the importance of edelfosine molecular structure in its effect on mitochondria. Raft disruption inhibited mitochondrial localization of the drug in cells and edelfosine-induced swelling in isolated mitochondria. Edelfosine promoted a redistribution of lipid rafts from the plasma membrane to mitochondria, suggesting a raft-mediated link between plasma membrane and mitochondria. Our data suggest that direct interaction of edelfosine with mitochondria eventually leads to mitochondrial dysfunction and apoptosis. These observations unveil a new framework in cancer chemotherapy that involves a link between lipid rafts and mitochondria in the mechanism of action of an antitumor drug, thus opening new avenues for cancer treatment.
Highlights
Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) is the prototype compound of a family of promising synthetic antitumor drugs collectively known as alkyl-lysophospholipid analogs or antitumor ether lipids.[3,4,5]
We found that edelfosine induced disruption of disruption of the mitochondrial transmembrane potential (DCm) and apoptosis in human cervix epithelioid carcinoma HeLa cells in a timedependent manner, assessed through 3,30-dihexyloxacarbocyanine iodide (DiOC6(3)) fluorescence and cell cycle analysis by flow cytometry (Figure 1a)
Through the synthesis of a number of fluorescent edelfosine analogs that preserved the proapoptotic features of the parent drug, we have found for the first time that an alkyllysophospholipid analog colocalizes with mitochondria, and that edelfosine affects mitochondria in a direct way
Summary
Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) is the prototype compound of a family of promising synthetic antitumor drugs collectively known as alkyl-lysophospholipid analogs or antitumor ether lipids.[3,4,5]. Edelfosine induces apoptosis in HeLa cells through a mitochondrial-mediated process.
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