Chemistry Reference
In-Depth Information
of redox sensitive pathways, that control cell proliferation and apoptosis, may be in play. Nuclear
factor kappa B (NF-
B) has been postulated to play a role in the initiation and the progression
of various cancers, particularly, in prostate cancer (Suh and Rabson 2004). The NF-
κ
B family
is composed normally of inactive transcription factors, which can be uninhibited by a number of
pathways that appear to be redox sensitive, since any number of antioxidant compounds can block
NF-
κ
, IL-1, lipopolysaccharide (LPS), or H
2
O
2
and its translocation to the
nucleus (Mercurio and Manning 1999). NF-
κ
B stimulation by TNF
α
B, once attached to various DNA response elements,
coordinates immune and inl ammatory responses as well as cell proliferation and survival espe-
cially at low levels of oxidative stress (Trachootham et al. 2008). Therefore its quiescence would
be consistent with the effect of lycopene on cell cycle and apoptosis. NF-
κ
B is over-expressed in
the androgen-insensitive prostate cell lines, PC-3 and DU-145 and prostate carcinoma xenographs,
whereas its expression is low in the hormone-responsive LNCaP cells (Paule et al. 2007, Suh and
Rabson 2004). Kim et al. found that lycopene (5-10
κ
M) inhibited the maturation of dendritic cells,
which are responsible for antigen-presentation in the stimulation of naive T lymphocytes. This sup-
pression of the immune response was associated with an inhibition of LPS-induced up-regulation of
p-ERK, p-p38, and p-JNK, all part of the redox-sensitive mitogen-activated protein kinase (MAPK)
signaling pathway that can stimulate the cytosolic liberation of NF-
μ
κ
B. Indeed, these investigators
B p65 nuclear translocation usually seen with LPS
stimulation (Kim et al. 2004). Dendritic cells are known to sustain some of the chronic inl am-
matory diseases (Poulter and Janossy 1985) and since inl ammation may be a component of pros-
tate carcinogenesis it may have a role in the whole prostate. Can lycopene or one of its oxidation
products act by changing the redox microenvironment? The only evidence that a change in redox
balance may be its mechanism of action comes from the studies of
found that 10
μ
M lycopene suppressed the NF-
κ
β
-carotene. Palozza et al. found
M) reduced the growth of HL-60 leukemic cells and was positively cor-
related with the ROS content of the cells. This effect could be prevented by the addition of 5
that
β
-carotene (10-30
μ
μ
M
α
-tocopherol pointing to a change in redox balance toward oxidation by some oxidation product
of
β
-carotene. DNA binding of NF-
κ
B was seen in cells treated with 10
μ
M
β
-carotene with only
3 h of incubation and this effect was greatly attenuated with
α
-tocopherol treatment (Palozza et al.
2003). These studies used pharmacologic doses of
β
-carotene and since apoptosis rather than cell
preservation was associated with NF-
B as
a transcription factor that can also stimulate cell death under severe oxidative stress was probably
in play. We would expect lycopene to have the same effect, at these high concentrations, since it has
an even greater propensity to oxidize in cell culture compared to
κ
B binding in these experiments, the dual nature of NF-
κ
β
-carotene. However, Huang et al.
observed that 1-10
B to binding sites
in the MMP-9 promotor (MMP-9 is a matrix metalloproteinase responsible for tumor invasion and
angiogenesis) in SK-Hep-1 human hepatoma cells and was not redox dependent. The evidence for
some other mechanism that shifts the redox balance in these experiments was (1) coincubation with
H
2
O
2
did not limit lycopene's inhibitory effect at physiologic concentrations even though it abol-
ished lycopene's antioxidant activity and (2) incubation with
μ
M lycopene induced the inhibition of direct binding of NF-
κ
-carotene had the same antioxidant
effect as lycopene but had no effect on the inhibition of cell invasion. They concluded that lycopene
action was likely associated with effects on the IGF signaling pathway (Huang et al. 2007).
Nuclear factor-E2 related factor 2 (Nrf2) is another nuclear transcription factor that can be found
in its inactivated state in the cytoplasm. Oxidative stress and electrophiles are the major activa-
tors of Nrf2, which translocates to the nucleus and heteromerizes with small Maf proteins that
then bind to an antioxidant response element (ARE) for over 200 genes involved in the synthesis
of proteins that act as antioxidants, phase II detoxii cation enzymes, proteosomes, heat-shock pro-
teins, and glutathione-synthesis proteins (Trachootham et al. 2008). Ben-Dor et al. explored the
effect of tomato carotenoids on this system in breast cancer MCF-7 and hepatic cancer HepG
2
cells.
Lycopene (6
β
M), more so than phytoene, astaxanthin, or tert-butylhydroquinone (tBHQ), a well-
known antioxidant and ARE activator, produced a three- to fourfold activation of the reporter gene
for
μ
γ
-glutamylcysteine synthase and NAD(P)H:quinone oxidoreductase, both Phase II enzymes
Search WWH ::
Custom Search