Pyrrolidine dithiocarbamate, a potent inhibitor of nuclear factor kappa B (NF-kappa B) activation, prevents apoptosis in human promyelocytic leukemia HL-60 cells and thymocytes.
We examined the effect of pyrrolidine dithiocarbamate (PDTC), which potently blocks the activation of nuclear factor kappa B (NF-kappa B), on the induction of apoptosis by a variety of agents. Treatment of a human promyelocytic leukemia cell line, HL-60, with 10 micrograms/mL etoposide or 2 microM 1-beta-D-arabinofuranosylcytosine induced NF-kappa B activation within 1 hr and subsequently caused apoptosis within 3-4 hr. The simultaneous addition of 50-500 microM PDTC with these agents blocked NF-kappa B activation and completely abrogated both morphologically apoptotic changes and internucleosomal DNA fragmentation for up to 6 hr. However, PDTC failed to inhibit the endonuclease activity contained in the whole cell lysates. The inhibitory effect of PDTC was also observed in etoposide- and dexamethasone-induced apoptosis in human thymocytes at a concentration of 1-10 microM. Since PDTC has both antioxidant and metal-ion chelating activities, we tested the effects of N-acetyl-L-cysteine (NAC) (antioxidant) or o-phenanthroline (OP) (metal-ion chelator) on the induction of apoptosis. Pretreatment of HL-60 cells or thymocytes with 100-500 microM OP for 2 hr, but not 10-60 mM NAC, suppressed subsequent occurrence of apoptosis induced by etoposide. These results suggest that the activation of NF-kappa B plays an important role in the apoptotic process of human hematopoietic cells.
Bessho
R
R
Department of Pediatrics, Faculty of Medicine, Kyoto University, Japan.
Matsubara
K
K
Kubota
M
M
Kuwakado
K
K
Hirota
H
H
Wakazono
Y
Y
Lin
Y W
YW
Okuda
A
A
Kawai
M
M
Nishikomori
R
R
D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D003561:Cytarabine / Q000494:pharmacology; D004720:Endonucleases / Q000037:antagonists & inhibitors; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009838:Oligodeoxyribonucleotides; D010618:Phenanthrolines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D013859:Thiocarbamates / Q000494:pharmacology*; D013950:Thymus Gland / Q000166:cytology; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D010618:Phenanthrolines; D011759:Pyrrolidines; D013859:Thiocarbamates; D003561:Cytarabine; C020972:pyrrolidine dithiocarbamic acid; D005047:Etoposide; D004720:Endonucleases; C025205:1,10-phenanthroline; D000111:Acetylcysteine