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mammary (MCF-7 and T-47D) and endometrial (ECC-1) cancer cells through down-regulation of
cyclin D1 and cyclin D3. The reduction in cyclin D1 levels by lycopene has been suggested to have
two consequences. The i rst one is a direct effect causing reduction in cyclin D-CDK4 complexes
resulting in a decrease of both CDK4 and CDK2 kinase activity and in a reduction of the hypophos-
phorylation of pRb. The second one is a retention of p27 in cyclin E-CDK2 complexes, an indirect
effect that leads to the inhibition of CDK2 activity (Nahum et al., 2001).
In a recent study, LNCaP and PC3 prostate cancer cells treated with lycopene-based agents have
been reported to undergo mitotic arrest. Lycopene's antiproliferative effects were likely achieved
through a block in G1/S transition mediated by decreased levels of cyclins D1 and E and cyclin-
dependent kinase4 and suppressed retinoblastoma phosphorylation (Ivanov et al., 2007).
We recently reported that tomato added to cultured colon (HT-29 and HCT-116) cancer cells by
an
in vitro
digestion procedure was able to induce an arrest of cell cycle progression at the G0/G1
phase (Palozza et al., 2007a). Such an effect was accompanied by a dose-dependent decrease in the
expression of cyclin D1. Although tomato digestates contain a complex mix of compounds besides
lycopene, including a large variety of micronutrients and microcostituents, such as polyphenols and
other non provitamin A carotenoids, this observation seems to support the notion that lycopene may
be a molecule that is extremely important in the regulation of intracellular levels of cyclin D.
Similarly, lycopene was also able to inhibit cell cycle progression at the G0/G1 phase and to
reduce cell proliferation by a mechanism involving cyclin D1 in normal cells. It has been reported
that, after the stimulation of synchronized human normal prostate epithelial cells with growth
factors, cyclin D1 protein expression increases in lycopene-untreated cells. Such an increase was
lower or even absent following treatment with lycopene at the concentration of 0.5 mmol/L and
5.0 mmol/L, respectively. Interestingly, it was specii c for cyclin D1, since cyclin E levels remained
constant and were unaffected by lycopene treatment (Obermüller-Jevic et al., 2003).
Moreover, we recently reported that lycopene was able to enhance the arrest of cell cycle pro-
gression induced by TAR in RAT-1 immortalized i broblasts. TAR-exposed cells treated with lyco-
pene showed a delay in cell cycle at the G0/G1 phase and a concomitant reduction in S phase. Such
effects were accompanied by a dose-dependent decrease in cyclin D1 levels. On the other hand,
i broblasts treated with lycopene alone showed the same effects, although to a lower extent. The
down-regulation of cyclin D1 observed in this study was dose-dependent and occurred at lycopene
concentration achievable
in vivo
after carotenoid supplementation (Palozza et al., 2005b).
In accord with these
in vitro
studies, treatment with lycopene
in vivo
has been also reported to
induce modulatory effects on cyclin D1 expression. It has been reported that smoke exposure sub-
stantially decreased the levels of p21
Waf1/Cip1
and increased those of cyclin D1 and proliferating cel-
lular nuclear antigen (PCNA) in gastric mucosa from ferrets. Supplementation of ferrets with either
low or high doses of lycopene prevented the changes in p21
Waf1/Cip1
, cyclin D1, and PCNA caused by
smoke exposure in a dose-dependent fashion (Liu et al., 2006).
Although further studies are needed to clarify the mechanism(s) of lycopene interference with
cell signaling leading to down-regulation of cyclin D1 and ultimately to cell cycle arrest in both
normal and tumor cells, these reports suggest that the reduction in cyclin D1 by lycopene treatment
may be a key event in the ability of the carotenoid to arrest cell cycle progression.
The regulation of cell cycle-related proteins by other carotenoids is less investigated.
In a recent study, the antiproliferative effect of different carotenoids, including b-carotene, lyco-
pene and lutein, on PCNA and cyclin D1 expression in human KB cells have been studied. The
results indicate that carotenoids suppressed cell growth by acting as inhibitors of the expressions of
PCNA and cyclin D1, although in a different extent (Cheng et al., 2007). On the other hand, b-car-
otene was able to induce a cell cycle delay in G2/M phase by decreasing the expression of cyclin A
in human colon adenocarcinoma cells (Palozza et al., 2002a).
Excentric cleavage products of b-carotene inhibited the growth of estrogen receptor positive and
negative breast cancer cells through the down-regulation of cell cycle regulatory proteins, such as
E2F1 and Rb and through the inhibition of AP-1 transcriptional activity (Tibaduiza et al., 2002).
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