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Blood, 1 June 2001, Vol. 97, No. 11, pp. 3544-3551
NEOPLASIA
Induction of mitochondrial changes in myeloma cells by
imexon
Katerina Dvorakova,
Caroline N. Waltmire,
Claire M. Payne,
Margaret E. Tome,
Margaret M. Briehl, and
Robert
T. Dorr
From the Arizona Cancer Center, Department of
Microbiology and Immunology, and Department of Pathology, University of
Arizona, Tucson.
Imexon is a cyanoaziridine derivative that has antitumor activity
in multiple myeloma. Previous studies have shown that imexon induces
oxidative stress and apoptosis in the RPMI 8226 myeloma cell line. This
study reports that imexon has cytotoxic activity in other malignant
cell lines including NCI-H929 myeloma cells and NB-4 acute
promyelocytic leukemia cells, whereas normal lymphocytes and U266
myeloma cells are substantially less sensitive. Flow cytometric
experiments have shown that imexon treatment is associated with the
formation of reactive oxygen species (ROS) and the loss of
mitochondrial membrane potential (  m) in
imexon-sensitive myeloma cell lines and NB-4 cells. In contrast,
reduction of m and increased levels of ROS were not
observed in imexon-resistant U266 cells. Treatment of imexon-sensitive
RPMI 8226 cells with the antioxidant N-acetyl-L-cysteine
(NAC) protects cells against these effects of imexon. Mitochondrial
swelling was observed by electron microscopy in RPMI 8226 myeloma cells
treated with 180 µM imexon as early as 4 hours. Damage to
mitochondrial DNA was detected by a semiquantitative polymerase chain
reaction assay in imexon-treated RPMI 8226 cells; however, nuclear DNA
was not affected. Finally, partial protection of RPMI 8226 cells
against the imexon effects was achieved by treatment with
theonyltrifluoroacetone, an inhibitor of superoxide production at
mitochondrial complex II. These changes are consistent with
mitochondrial oxidation and apoptotic signaling as mediators of the
growth inhibitory effects of imexon. Interestingly, oxidative damage
and decrease of m induced by imexon highly correlates
with sensitivity to imexon in several myeloma cell lines and an acute
promyelocytic leukemia cell line.
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