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Department of Nutrition, School of Public Health and School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7400, USA
1Correspondence: Department of Nutrition, CB #7400, 2213 McGavran-Greenberg Hall, University of North Carolina, Chapel Hill, NC 27599-7400, USA. E-mail: steven_zeisel{at}unc.edu
The mechanism of induction of apoptosis by the novel anti-cancer
drug
1-O-octadecyl-2-methyl-rac-glycero-3-phosphocholine
(ET-18-OCH3) was investigated in p53-defective SV40
immortalized rat hepatocytes (CWSV1). Exposure to 12 µM
ET-18-OCH3 for 36 h induced apoptosis as determined
using classical morphological features and agarose gel electrophoresis
of genomic DNA. Increased levels of reactive oxygen species (ROS) were
detected spectrophotometrically using a nitroblue tetrazolium (NBT)
assay in cells treated with ET-18-OCH3. Both the increased
generation of ROS and the induction of apoptosis were inhibited when
cells were treated concurrently with ET-18-OCH3 in the
presence of the antioxidant 
-tocopherol. Similar results were
achieved when cells were switched acutely to choline-deficient (CD)
medium in the presence of the antioxidant. The possible role of
mitochondria in the generation of ROS was investigated. Both
ET-18-OCH3 and CD decreased the phosphatidylcholine (PC)
content of mitochondrial and associated membranes, which correlated
with depolarization of the mitochondrial membrane as analyzed
using 5,5',6,6'-tetramethylbenzimidazolcarbocyanine iodide
(JC-1), a sensitive probe of mitochondrial membrane potential.
Rotenone, an inhibitor of the mitochondrial electron transport chain,
significantly reduced the intracellular level of ROS and prevented
mitochondrial membrane depolarization, correlating with a reduction of
apoptosis in response to either ET-18-OCH3 or CD. Taken
together, these results suggest that the form of p53-independent
apoptosis induced by ET-18-OCH3 is mediated by alterations
in mitochondrial membrane PC, a loss of mitochondrial membrane
potential, and the release of ROS, resulting in completion of
apoptosis.—Vrablic, A. S., Albright, C. D., Craciunescu,
C. N., Salganik, R. I., Zeisel, S. H. Altered
mitochondrial function and overgeneration of reactive oxygen species
precede the induction of apoptosis by
1-O-octadecyl-2-methyl-rac-glycero-3-phosphocholine in
p53-defective hepatocytes.
Key Words: apoptosis • cancer • edelfosine • mitochondria • phosphatidylcholine • reactive oxygen species
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