Genistein induces apoptosis in immature human thymocytes by inhibiting topoisomerase-II.
The toxicity of genistein, an inhibitor of tyrosine kinases and topoisomerase-II, on human thymocytes was investigated. Genistein induced marked chromatin fragmentation indicative of apoptosis in human thymocyte cultures. Genistein-induced thymocyte apoptosis is unlikely due to an inhibition of basal tyrosine kinase activity, since another tyrosine kinase inhibitor, herbimycin A, does not induce thymocyte apoptosis, whereas other topoisomerase-II inhibitors do. The thymocyte subpopulation most sensitive to genistein-induced apoptosis exhibited a CD3-CD4+CD8+ phenotype. This subpopulation of thymocytes is also sensitive to glucocorticoid-induced apoptosis; however, differences between genistein- and glucocorticoid-induced apoptosis were noted. In particular, unlike glucocorticoid-induced apoptosis, genistein-induced apoptosis does not involve changes in [Ca2+]i and cannot be blocked by activation of protein kinase C.
McCabe
M J
MJ
Department of Toxicology, Karolinska Institute, Stockholm, Sweden.
Orrenius
S
S
D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones; D002478:Cells, Cultured; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D019833:Genistein; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007529:Isoflavones / Q000494:pharmacology*; D007700:Kinetics; D047029:Lactams, Macrocyclic; D008775:Methylprednisolone / Q000494:pharmacology; D009675:Novobiocin / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D013997:Time Factors; D059005:Topoisomerase II Inhibitors
D016227:Benzoquinones; D002843:Chromatin; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D011809:Quinones; D059005:Topoisomerase II Inhibitors; D009675:Novobiocin; D017828:Rifabutin; D015240:Phorbol 12,13-Dibutyrate; D005047:Etoposide; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D013755:Tetradecanoylphorbol Acetate; D008775:Methylprednisolone