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Effects of Lycopene Supplementation in Patients
with Localized Prostate Cancer
OMER KUCUK,*
,1
FAZLUL H. SARKAR,†ZORA DJURIC,* WAEL SAKR,† MICHAEL N. POLLAK,¶
F
RED KHACHIK,+ MOUSUMI BANERJEE,§ JOHN S. BERTRAM,** AND DAVID P. WOOD,JR‡
*Division of Hematology and Oncology, †Departments of Pathology, ‡Urology, and §Biostatistics,
Wayne State University, and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201;
¶Department of Medicine, McGill University and Jewish General Hospital, Montreal, Quebec H3T
1E2, Canada; +Joint Institute for Applied Nutrition, Department of Chemistry and Biochemistry,
University of Maryland, College Park, Maryland 20742; and **Cancer Research Center of Hawaii,
University of Hawaii, Honolulu, Hawaii 96813
Epidemiological studies have shown an inverse association be-
tween dietary intake of lycopene and prostate cancer risk. We
conducted a clinical trial to investigate the biological and clini-
cal effects of lycopene supplementation in patients with local-
ized prostate cancer. Twenty-six men with newly diagnosed
prostate cancer were randomly assigned to receive a tomato
oleoresin extract containing 30 mg of lycopene (n = 15) or no
supplementation (n = 11) for 3 weeks before radical prostatec-
tomy. Biomarkers of cell proliferation and apoptosis were as-
sessed by Western blot analysis in benign and cancerous pros-
tate tissues. Oxidative stress was assessed by measuring the
peripheral blood lymphocyte DNA oxidation product 5-hydroxy-
methyl-deoxyuridine (5-OH-mdU). Usual dietary intake of nutri-
ents was assessed by a food frequency questionnaire at base-
line. Prostatectomy specimens were evaluated for pathologic
stage, Gleason score, volume of cancer, and extent of high-
grade prostatic intraepithelial neoplasia. Plasma levels of lyco-
pene, insulin-like growth factor-1, insulin-like growth factor
binding protein-3, and prostate-specific antigen were measured
at baseline and after 3 weeks of supplementation or observa-
tion. After intervention, subjects in the intervention group had
smaller tumors (80% vs 45%, less than 4 ml), less involvement
of surgical margins and/or extra-prostatic tissues with cancer
(73% vs 18%, organ-confined disease), and less diffuse involve-
ment of the prostate by high-grade prostatic intraepithelial neo-
plasia (33% vs 0%, focal involvement) compared with subjects
in the control group. Mean plasma prostate-specific antigen lev-
els were lower in the intervention group compared with the con-
trol group. This pilot study suggests that lycopene may have
beneficial effects in prostate cancer. Larger clinical trials are
warranted to investigate the potential preventive and/or thera-
peutic role of lycopene in prostate cancer.
Exp Biol Med 227:881–
885, 2002
Key words: lycopene; prostate cancer; chemoprevention; treat-
ment; connexin; tomato carotenoids
E
pidemiological studies have shown an inverse asso-
ciation between dietary intake of lycopene and pros-
tate cancer risk (1). Possible mechanisms by which
lycopene may prevent cancer include 1) inhibition of
growth and induction of differentiation in prostate cancer
cells (2–6); 2) upregulation of tumor suppressor protein
Cx43 and increased gap junctional intercellular communi-
cation (7–11); and 3) prevention of oxidative DNA damage
(12, 13).
Lycopene increases gap-junctional intercellular com-
munication by increasing expression of gap junctional gene,
connexin 43 (7–9). This action correlates strongly with the
ability of lycopene and other carotenoids to suppress neo-
plastic transformation in model cell culture systems (9).
This action of carotenoids has been proposed to have
mechanistic significance by enabling the transfer of growth-
regulatory signals between normal growth-inhibited cells
and pre-neoplastic cells. Indeed, when neoplastic cells were
forced into junctional communication with quiescent nor-
mal cells, the neoplastic cells became growth arrested in
direct proportion to their extent of junctional communica-
tion (14). Progressive decreases with disease severity in the
expression of Cx43 have been reported in the human pros-
tate (15), and there is evidence in prostatic carcinoma cell
lines that some of this loss of junctional communication
may result from defects in assembly of Cx43 protein into
gap junctions (16). When functional communication was
restored in a human prostatic carcinoma cell line, cells had
more normal differentiation, reduced proliferation, and sup-
pressed tumorigenicity (17).
Insulin-like growth factors (IGFs) have mitogenic and
antiapoptotic effects on normal and transformed prostate
epithelial cells (18–20). IGF-1 is an important mitogen for
prostate cells. Insulin-like growth factor binding proteins
(IGFBPs) have opposing actions, in part by binding IGF-1
but also by direct inhibitory effects on target cells (18). In
recent epidemiological studies, relatively high plasma
1
To whom all correspondence should be addressed at Division of Hematology and
Oncology, 3990 John R, 5 Hudson, Detroit, MI 48201. E-mail: kucuko@karmanos.
org
1535-3702/02/22710-0881$15.00
Copyright © 2002 by the Society for Experimental Biology and Medicine
LYCOPENE IN LOCALIZED PROSTATE CANCER 881
IGF-1 and low IGFBP-3 levels were independently associ-
ated with greater risk of prostate cancer (21–25). Two- to
4-fold elevated risks have been observed for prostate cancer
in men in the top quartile of IGF-1 relative to those in the
bottom quartile, and low levels of IGFBP-3 were associated
with an approximate doubling of risk (21).
Despite the inverse association between lycopene in-
take and prostate cancer observed in epidemiological stud-
ies, no clinical intervention studies have previously been
reported showing the effect of lycopene supplements in men
with prostate cancer. We conducted a pilot study investi-
gating the effect of lycopene supplementation on the pros-
tate tissues and on serum levels of prostate-specific antigen
(PSA), IGF-1, and IGFBP-3 in patients with localized pros-
tate cancer. We hypothesized that lycopene supplementa-
tion would decrease growth and induce apoptosis in prema-
lignant and malignant prostate cells by up-regulating Cx43,
downregulating IGF-1 and decreasing the ratio of bcl-2/bax
in patients with localized prostate cancer.
Clinical Trial of Lycopene in Prostate Cancer
We conducted a randomized, two-arm clinical interven-
tion study in 35 patients with clinical stages T1 or T2 pros-
tate cancer who were scheduled to undergo radical prosta-
tectomy. Nine patients were excluded from analysis because
they had incorrect diagnosis (one patient), or dropped out
after randomization (two patients) or had previous hormone
therapy (six patients). Data were collected from 26 eligible
patients who were randomly assigned to the lycopene arm
(n ⳱ 15) or the control arm (n ⳱ 11) of the study. Detailed
description of the methodology and the results of this trial
have been published elsewhere (26).
Subjects were randomly assigned to either lycopene
supplementation or no intervention for 3 weeks before sur-
gery. Blood samples were collected and food frequency
questionnaires were obtained at baseline. Another blood
sample was obtained for biomarker studies after 3 weeks of
intervention before radical prostatectomy. Entire prostate
glands were resected and specimens were evaluated for
pathologic stage, Gleason score, the volume of prostate can-
cer as well as the extent of high-grade prostatic intraepithe-
lial neoplasia (HGPIN). Tissue levels of Cx43, bcl-2, and
bax were assessed by Western blotting in benign and ma-
lignant tissue samples. Plasma and tissue levels of carot-
enoids were measured by HPLC. Plasma levels of IGF-1
and IGFBP-3 were measured by enzyme-linked immuno-
sorbent assay. Peripheral blood lymphocyte levels of 5-hy-
droxymethyl-deoxyuridine (5-OhmdU) were measured by
gas chromatography-mass spectrometry.
Subjects randomized to the intervention arm were
asked to take a tomato oleoresin extract containing 15 mg of
lycopene (Lyc-O-Mato
®
, LycoRed Natural Products Indus-
tries, Beer-Sheva, Israel) twice daily. Subjects randomized
to the control arm were asked to continue their regular diet
and were given the NCI recommendations to increase daily
fruit and vegetable intake to five servings a day.
After 3 weeks of intervention or no intervention, all
subjects underwent radical prostatectomy with removal of
the entire prostate gland, seminal vesicals, and surrounding
soft tissues. Fresh tissue samples were obtained with the
exact anatomic source of each sample clearly indicated on a
specimen diagram for subsequent microscopic confirma-
tion. In cases where gross identification of the tumor was
difficult to establish, a frozen section slide of the suspected
area was generated and stained with hematoxylin and eosin
to guide the acquisition protocols. When possible,1gof
tissue from benign areas of the gland was kept frozen for
lycopene analysis. Appropriate tissue samples were taken
for Western blotting and for histologic examination. Tissue
samples obtained from benign and malignant parts of the
glands were stored at −70°C until biomarker studies were
performed. The specimens were then entirely embedded in
paraffin, step-sectioned, and microscopically examined by
the study pathologists.
Changes in clinical parameters are shown in Table I.
Mean plasma PSA levels decreased by 18% in the interven-
tion group whereas they increased by 14% in the control
group over the study period (P ⳱ 0.22). In the intervention
group, 11 of 15 patients (73%) had involvement of surgical
margins and/or extra-prostatic tissues with cancer, com-
pared with 2 of 11 patients (18%) in the control group (P ⳱
0.02). Twelve of 15 patients (80%) in the lycopene group
had tumors that measured 4 ml or less compared with 5 of
11 (45%) in the control group (P ⳱ 0.22). Multifocal and/or
diffuse involvement by HGPIN was observed in 10 of 15
subjects (67%) in the lycopene group compared with all 11
subjects (100%) in the control group (P ⳱ 0.05).
Sufficient malignant tissues were available for analysis
in four subjects from the lycopene group and in four sub-
jects from the control group. The level of Cx43 protein was
0.63 ± 0.19 optical density (OD) units in the lycopene group
compared with the 0.25 ± 0.08 OD units in the control group
(P ⳱ 0.13). The expression of cell cycle regulatory pro-
teins, bcl-2 and bax, were not significantly different be-
tween the two groups, although bax level of the lycopene
group (1.05 ± 0.29) was higher than the control group (0.68
± 0.18).
Tissue samples from benign parts of the gland were
available for biomarker analysis in eight subjects in the
intervention group and six subjects in the control group.
Cx43 level was 0.64 ± 0.12 in the lycopene group compared
with 0.51 ± 0.10 in the control group. The expression of
bcl-2 was 0.63 ± 0.04 in the intervention group and 0.58 ±
0.04 in the control group, and the expression of bax was
0.62 ± 0.10 in the intervention group and 0.79 ± 0.11 in the
control group. None of the differences in the biomarkers of
the two groups were statistically significant.
Plasma samples were available from 13 subjects in the
intervention group and 10 subjects in the control group.
882 LYCOPENE IN LOCALIZED PROSTATE CANCER
Mean plasma levels of IGF-1 decreased by from 233 ± 21
ng/ml to 169 ± 23 ng/ml in the lycopene group (P ⳱
0.0002) and from 199 ± 20 ng/ml to 140 ± 16 ng/ml in the
control group (P ⳱ 0.0003). Interestingly, IGFBP-3 levels
also decreased in both intervention and control groups dur-
ing the study period. Plasma IGFBP-3 levels of intervention
group decreased from 5230 ng/ml to 3924 ng/ml and control
group decreased from 5200 ng/ml to 4070 ng/ml, which
were statistically significant (P ⳱ 0.0002 and P ⳱ 0.0001,
respectively).
In the intervention group, plasma lycopene level in-
creased in 5 of 11 patients, whereas only one of six subjects
in the control group had an increase (Fisher’s exact test, P
⳱ 0.33). The level of post-intervention plasma lycopene
was 23.5 g/dl in the intervention group and 17.5 g/dl in
the control group (P ⳱ 0.15). However, there was no sig-
nificant difference between the two groups with regard to
percent change of plasma lycopene level because of great
variability in plasma lycopene levels and small numbers of
subjects in each group. Prostatic tissue lycopene levels were
47% higher in the intervention group (0.53 ± 0.03 ng/g of
prostate tissue) compared with the control group (0.36 ±
0.06), which was a significant difference (P ⳱ 0.02) despite
the small number of samples (n ⳱ 8).
Peripheral blood lymphocyte levels of 5-OHmdU were
similar in both groups before and after intervention. There
were no differences between the groups with respect to
baseline intake of nutrients assessed by food frequency
questionnaire.
Discussion and Conclusions
The results suggest that 30 mg of lycopene taken daily
for 3 weeks may be sufficient to modulate prostate cancer.
The microscopic extension of prostate cancer to surgical
margins and/or to extra-prostatic tissues appeared to have
decreased as a result of lycopene supplementation. This
finding has potential clinical implications as extension of
tumor to surgical margins identifies a group of patients with
poor prognosis. Patients in the lycopene group had a de-
crease in the plasma PSA level, which is a clinical param-
eter of prostate cancer burden. These results suggest that
lycopene may have an antitumor effect and perhaps be use-
ful as an adjunct to standard treatments of prostate cancer,
such as surgery, radiation therapy, hormones and chemo-
therapy. In addition, lycopene supplementation appears to
have reduced the diffuse involvement of the prostate gland
with HGPIN, which is a precursor of prostate cancer (27),
suggesting that lycopene may have a role in the prevention
of prostate cancer.
The mechanism of the clinical effects of lycopene re-
mains to be elucidated. Upregulation of Cx43 expression
would be a potential explanation. However, although there
was an increase in the expression of Cx43 in tumor tissue in
the intervention group, it did not reach statistical signifi-
cance, perhaps because of the small number of subjects.
When the results from all 35 randomized subjects (including
the nine subjects who were excluded from analysis because
of protocol violation) are analyzed, Cx43 expression was
significantly higher in the tumors from patients in the lyco-
pene group (P < 0.05). Increased expression of Cx43 and
increased junctional communication have previously been
shown to occur after treatment of human and murine cells in
culture with lycopene (8). Upregulated junctional commu-
nication has been linked to decreased proliferation in nor-
mal and pre-neoplastic cells (28). Therefore, our results sug-
gest that lycopene supplementation may decrease the
growth of prostate cancer, perhaps by upregulating Cx43.
However, because of small sample size, no definitive
conclusions can be reached. Clearly, larger clinical trials
are needed to determine the efficacy as well as the appro-
Table I. Change in Clinical Parameters in Intervention (n = 15) and Control (n = 11) Groups
Intervention Control P value
PSA level (mean ± SE, ng/ml)
a
Pre-intervention 6.89 ± 0.81 6.74 ± 0.88
Post-intervention 5.64 ± 0.87 7.65 ± 1.78 0.25
b
High-grade PIN (n)
Focal 5 0
Multifocal/diffuse 10 11 0.05
Gleason score
6ⱕ 74
>6 8 7 0.70
Tumor volume (cm
3
)
4ⱕ 12 5
>4 3 6 0.22
Surgical stage (n)
Confined to prostate 11 2
Not confined to prostate
c
4 9 0.02
a
SE denotes standard error.
b
P value is for comparing the change from pre- to post-intervention PSA in the two groups.
c
Resection margins are positive and/or extra-prostatic invasion is present.
LYCOPENE IN LOCALIZED PROSTATE CANCER 883
priate dose and duration of lycopene supplementation in
men with prostate cancer or high risk of developing prostate
cancer.
It should be noted that the lycopene preparation that
was used in this study was a mixture of tomato carotenoids
and other tomato phytochemicals (Table II). Although ly-
copene was the predominant carotenoid in the capsules,
there were significant amounts of phytoene and phytofluene
and other bioactive compounds. It is possible that the com-
bination of the phytochemicals present in the tomato extract
was responsible for the observed clinical effects rather than
lycopene alone. There are in vitro data suggesting synergis-
tic effects of lycopene with phytoene, phytofluene and beta-
carotene against prostate cancer cells (personal communi-
cation, Yoav Sharoni and Yossi Levy).
The differences observed in bioavailability and re-
sponse to Lycomato preparation in this study are not easily
explained because the preparation contains the natural to-
mato oleoresin present in tomato matrix in the Lyc-O-
Mato® capsules used in this study. Previous studies have
shown excellent bioavailability of lycopene from this prepa-
ration (29). However, it is possible that the fat and other
nutrients in the diet might have influenced the bioavailablity
of lycopene in our study population.
Future Directions
Dose–response to lycopene should be investigated in
subjects with localized and advanced prostate cancer. Clini-
cal trials should be conducted in patients with HGPIN or
elevated PSA but without a diagnosis of prostate cancer as
they are at a high risk of developing prostate cancer or
having occult disease. Lycopene could be compared with
other promising agents such as vitamin E, selenium or soy
in future clinical trials. We have found significant in vitro
(30, 31) and clinical activity with soy isoflavones (32). We
are currently conducting clinical trials investigating the ef-
fects of lycopene alone or in combination with soy isofla-
vones in patients with advanced prostate cancer. We plan to
investigate the effects of lycopene alone and in combination
with other tomato carotenoids in patients with prostate can-
cer. Lycopene should also be combined with vitamin E (33)
and selenium (34) in future clinical trials.
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Table II. Composition of Lyc-O-Mato® Capsules
Component
Percentage (w:w) in 250 mg
Lyc-O-Mato® capsule
Carotenoids
Lycopene 5.8–6.2
Phytoene 0.5–0.7
Phytofluene 0.5–0.6
-carotene 0.1–0.2
Total 6.9–7.7
Other components
Tocopherols 1.5–2.5
Phospholipids 14–16
Phytosterols 0.5–0.7
Tomato oil 73–76
884 LYCOPENE IN LOCALIZED PROSTATE CANCER
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