|
Synergistic
action of genistein and cisplatin on growth inhibition and cytotoxicity of human
medulloblastoma cells
Khoshyomn S, Manske GC, Lew SM, Wald SL, Penar PL
Division of Neurosurgery, Department of Surgery, University of Vermont College
of Medicine, Burlington, VT 05401, USA
Objective. Recent experimental data have shown that dietary soy isoflavones such
as genistein can significantly suppress invasiveness and growth of a number of
human malignancies.
In this study we examined whether genistein, at a
concentration typical of plasma levels following soy formula intake, in
combination with cisplatin or vincristine exhibited an additive or synergistic
inhibitory effect on the growth of medulloblastoma cells.
Methods. Three human
medulloblastomas cell lines (HTB-186, CRL-8805 and MED-1) were treated with
genistein at 6 microM, the maximum reported dietary plasma level in children,
combined with cisplatin (0-10 microM) or vincristine (0-1 microM).
Monolayer
cell growth and cytotoxicity, as measured by colonigenic survival in soft
agarose, were then compared in control and drug-treated cultures.
Presence of
apoptosis, using the DNA ladder assay and laser scanning cytometry, was
investigated in all cell lines at those concentrations at which an enhancement
of antiproliferative effect of cisplatin and vincristine in presence of
genistein was observed.
Results. Genistein at 6 microM led to a 2.8-fold
increase in the monolayer growth inhibitory effect of cisplatin (0.05 microM) in
HTB-186 cells (p = 4.5 x 10(-4) by one-tailed t test).
Genistein increased
colonigenic survival inhibition of HTB-186 2.6-fold at the same cisplatin
concentration (p = 1.5 x 10(-4)).
Genistein caused a 1. 3-fold increase in
antiproliferative effect of cisplatin (0.5 microM) in CRL-8805 cells (p = 3.1 x
10(-4)).
Similarly the inhibition of colonigenic survival was enhanced 2.0-fold
in CRL-8805 (p = 1.22 x 10(-5)).
The addition of genistein to 0.5 microM
cisplatin led to a 1.7-fold increase in monolayer growth inhibition and 2.4-fold
increase in colonigenic survival inhibition of MED-1 cells (p = 8.3 x 10(-4) and
p = 1.1 x 10(-4) respectively).
These effects were primarily synergistic but
also additive in nature.
The combination of genistein and vincristine, as
compared to vincristine alone, caused a minimal-to-modest increase in
antiproliferative effect on medulloblastoma cells studied here.
We were unable
to detect apoptosis by two methodologies in any of the medulloblastoma lines
when genistein was combined with cisplatin or vincristine.
Conclusion. These
results indicate that genistein at typical dietary plasma levels can
significantly enhance the antiproliferative and cytotoxic action of cisplatin
and, to a lesser extent, vincristine.
The implication for treatment of
medulloblastomas of early childhood may be a reduction in the chemotherapeutic
dose recommendations of these agents and subsequently a decrease in the risk of
treatment sequelae for these patients.
Copyright 2000 S. Karger AG, Basel
PMID: 11096359 [PubMed - indexed for MEDLINE]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11096359&dopt=Abstract
|
