Carcinogenesis, Vol 19, 991-997, Copyright © 1998 by Oxford University Press
A Brown, P Jolly and H Wei
Genistein is a specific inhibitor of protein tyrosine kinase (PTK) and is
considered as a therapeutic candidate for various cancers. In this paper we
investigate the effects of genistein on cell proliferation and
differentiation in neuroblastoma (NB) cell lines and its possible mechanism
of action. Genistein substantially inhibited the growth of five (N2A, JC,
SKNSH, MSN and Lan5) of the six tumor cell lines examined in a
dose-dependent manner with an IC50 value of approximately 5 microg/ml. The
exception was GC cells. N2A cells were treated with genistein for 6 days
and exhibited morphological features of differentiation, as evidenced by
the development of dendritic extensions. Terminal deoxynucleotidyl
transferase (TDT) histochemical staining showed a significant elevation in
darkly stained nuclei in genistein-treated N2A cells compared with
controls, indicating the occurrence of apoptosis. Fluorescent quantitation
of DNA fragments confirmed apoptosis in genistein-treated N2A cells. To
further elucidate the possible mechanisms by which genistein modulates NB
cell growth and differentiation we investigated the effect of genistein on
the activities of PTK and mitogen-activated protein (MAP) kinase and N- myc
proto-oncogene expression in N2A cells. The results showed that genistein
down-regulated intrinsic PTK activity by approximately 33% and inhibited
insulin-like growth factor (IGF)-stimulated PTK activity by 75%. The effect
of genistein on the intrinsic activity of MAP kinase was insignificant. In
addition, genistein significantly reduced N-myc expression in a
dose-dependent fashion. Our study suggests that genistein arrests cell
growth and induces NB cell differentiation by mediating apoptosis and
modulating PTK activity and N-myc proto- oncogene expression.
ARTICLES
Genistein modulates neuroblastoma cell proliferation and differentiation through induction of apoptosis and regulation of tyrosine kinase activity and N-myc expression
Department of Environmental Health Sciences, University of Alabama, Birmingham 35294, USA.
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