Induction of apoptosis by T-2 toxin and other natural toxins in HL-60 human promyelotic leukemia cells.
Based on the DNA fragmentation profile in gel electrophoresis and the morphological changes in electron microscopy, the induction of apoptotic nuclear changes by mycotoxins and other microbial products, in total 31 chemicals, was investigated in HL-60 human promyelotic leukemia cells, along with the cytotoxicity tests with 3-[4,5-dimethylthiazol-zyl]-2,5-diphenyltetrazolium bromide (MTT) and trypan blue exclusion. Among the chemicals tested, trichothecenes (T-2 toxin, roridin A, nivalenol, deoxynivalenol), certain anthraquinones (luteoskyrin, skyrin, 2-hydroxyemodin), diketopiperazines (emethallicin A, emestrin), isocoumarins (ochratoxin A, citrinin), lactone (penicillic acid), dihydrobisfuran (aflatoxin B1), potassium ionophore (valinomycin), and an inhibitor of interleukin-2 synthesis (cyclosporin A) were positive for the induction of DNA fragmentation. No DNA fragmentation was observed under the present conditions with fumonisin B1, cyclic peptides (cyclochlorotine, phalloidin, microcystin-LR), certain anthraquinones (emodin, chrysophanol, rugulosin), and others (sterigmatocystin, cytochalasin A, griseofulvin, fusaric acid, kojic acid, rubratoxin B, butenolide, wortmannin, FK506, and sphingosine). The apoptotic changes in the cells exposed to T-2 toxin and luteoskyrin were confirmed by electron microscopic observation. Detailed experiments on dose and time dependencies revealed that T-2 toxin induced the apoptosis at 10 ng/ml (= 4 x 10(-8) M) levels within 2-6 hr without significant cytotoxicity evaluated by the dye exclusion and MTT.
Ueno
Y
Y
Faculty of Pharmaceutical Sciences, Science University of Tokyo, Japan.
Umemori
K
K
Niimi
E
E
Tanuma
S
S
Nagata
S
S
Sugamata
M
M
Ihara
T
T
Sekijima
M
M
Kawai
K
K
Ueno
I
I
D000880:Anthraquinones / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D008854:Microscopy, Electron; D009183:Mycotoxins / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013605:T-2 Toxin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D004273:DNA, Neoplasm; D009183:Mycotoxins; D010456:Peptides, Cyclic; D013605:T-2 Toxin