Induction of mitochondrial changes in myeloma cells by imexon.
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)
Dvorakova
K
K
Arizona Cancer Center, Department of Microbiology and Immunology, University of Arizona, 1515 N. Campbell Ave., Tucson, AZ 85724, USA.
Waltmire
C N
CN
Payne
C M
CM
Tome
M E
ME
Briehl
M M
MM
Dorr
R T
RT
D000096:Acetone / Q000031:analogs & derivatives / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects; D042963:Electron Transport Complex II; D005434:Flow Cytometry; D006588:Hexanones / Q000494:pharmacology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008214:Lymphocytes / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009101:Multiple Myeloma / Q000648:ultrastructure*; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors; D013876:Thiophenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000975:Antioxidants; D003574:Cytochrome c Group; D004272:DNA, Mitochondrial; D006588:Hexanones; D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D013876:Thiophenes; C429269:theonyltrifluoroacetone; D000096:Acetone; C014919:4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D000111:Acetylcysteine