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 (Deltapsi(m)) in
imexon-sensitive myeloma cell lines and NB-4 cells. In contrast, reduction of Deltapsi(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 microM
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 Deltapsi(m) induced by
imexon highly correlates with sensitivity to
imexon in several myeloma cell lines and an
acute promyelocytic leukemia cell line. (Blood. 2001;97:3544-3551)