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Lycopene and Soy Isoflavones in
Cancer Prevention
Omer Kucuk, MD
Professor of Medicine
Winship Cancer Institute
Emory University
Atlanta, Georgia, USA
NUTRITION AND
CANCER
Let food be your
medicine.
-Hippocrates
400 BC
Tomato consumption and cancer
72 studies identified (observational
studies)
57 reported inverse association
between tomato intake or blood
lycopene level and the risk of cancer
(at a definitive anatomic site)
35 of these inverse associations were
statistically significant
No study indicated a positive
association
Giovannucci E., 1999
Lycopene reduces the risk of various types of cancer
Statistically Significant Not Statistically Significant
Total
Oral, Larynx
Esophagus
Stomach
Colon
Rectum
Pancreas
Lung
Prostate
Bladder
Breast
Cervix
Ovary
Mesothelioma
Giovanucci, JNCI RR: 0.5 1 1.5
91, 317-331 1999
Convincing protective effect
lung, stomach, prostate
Suggestive protective effect
colon-rectum, pancreas, breast, cervix,
oral cavity, esophagus
The composition of tomato
water 94 % vitamin C 160-240 mg/kg
protein 0.7 % vitamin E 8 – 12 mg/kg
fat 0.3 %
lycopene 15 - 56 mg/kg
carbohydrat 3.1 %
fibre 1.2 % carotenoids 6 - 8 mg/kg
flavonoids 5 - 50 mg/kg
phenols 10 - 50 mg/kg
manganese 1 – 1.5 mg/kg
zinc 1 – 2.4 mg/kg
iron 4 - 5 mg/kg
copper 0.1-0.9 mg/kg
folates 150-390 g/kg
Effect of tomato product intake on
prostate cancer risk
1.10
tomato juice
1.00
Relative risk
0.90
tomato fruits
0.80
pizza
0.70
tomato sauce
0.60
0 1 2 3
Servings
Adapted from Giovanucci et al. JNCI 87, 1767 (1995)
Carotenoid intake and prostate cancer
1.10
1.00 b-carotene
Relative risk
0.90
0.80 lycopene
0.70
0.60
0 1 2 3 4 5
Carotenoid intake
Giovanucci et al. JNCI 87, 1767 (1995)
Steps in carotenoid biosynthesis
b-carotene
Lycopene
Neurosporene
-carotene
Phytofluene
Phytoene
Effect of tomato extract supplementation on IGF-I and
lycopene levels in colon cancer patients (Sharoni, Levy)
Baseline After supplementation
A. IGF-I B. Plasma lycopene
210 P< 0.001 N.S. 0.6 P< 0.05 N.S.
175
ng/ml
140 -6 0.4
µM
%
105
-29
70 % 0.2
35
0 0
lycopene placebo lycopene placebo
n=21 n=18 n=21 n=18
Astaxanthin and lycopene inhibit cancer cell proliferation
Mammary cancer Prostate cancer
MCF-7 MDA-231 LNCaP DU-145
Astaxanthin
Lycopene
cell growth (percent of control)
120 120 120 120
100 100 100 100
80 80 80 80
60 60 60 60
40 40 40 40
20 20 20 20
0 0 0 0
0 5 10 0 5 10 0 5 10 0 5 10
Carotenoid [M]
Androgen- and IGF-I-stimulated growth in LNCaP is
inhibited by astaxanthin and lycopene (Sharoni)
Control
[3H]thymidine incorporation (cpm)
1600 Astaxanthin
Lycopene
1200
800
400
0
No addition DHT IGF-I
Lycopene and astaxanthin reduce PSA level in
prostate cancer cells (Sharoni, Levy)
0h 6h 12 h 24 h 36 h
1 2 3 1 2 3 1 2 3 1 2 3
16 Testosterone (1)
Arbitrary units
12
Tes+ astaxanthin (3)
8
4
Tes+lycopene (2)
0
12 24 36
Time after testosterone (hour)
The synergistic effect at low concentration of
carotenoids in LNCaP prostate cancer cells
Thymidine incorporation (cpm)
1500
Phytoene
1000
Lycopene
500
+Lycopene
0.2 M
0
0 1 2 3 4
carotenoid [µM]
Tomato carotenoids activate expression from
nuclear receptor RE (Sharoni, Levy)
100
30
atRA RAR Response
Reporter activity (%)
20 Element (DR-5)
10
0
100
Cigl. PPARg Response
80
Element (DR-1)
60
40
20
0
agonist lycopene phytoene b-carotene
Pilot study of lycopene in patients
with prostate cancer
MEN SCHEDULED FOR RADICAL PROSTATECTOMY
|
BIOPSY AND BLOOD SAMPLES
|
R A N D O M I Z E
| |
LYCOPENE* 30 MG/DAY NO LYCOPENE
| |
PROSTATECTOMY AND BLOOD SAMPLES AFTER 3
WEEKS OF INTERVENTION
*Lyc-O-Mato
Carotenoid content of
Lyc-O-Mato® capsule
All-E(trans)-Lycopene 13.50 mg
5-Z(cis)-Lycopene 1.05 mg
5Z,5'Z-Lycopene 0.45 mg
b-Carotene 0.16 mg
g-Carotene 0.09 mg
-Carotene 0.24 mg
Phytofluene 1.03 mg
Phytoene 1.16 mg
Typical carotenoid profile of a prostate
specimen after 3 weeks on 30 mg/d Lycomato
Pathologic Tumor Stage
LYCOPENE CONTROL
GROUP GROUP
(N=15) (N=11) p
---------------------------------------------------------------
Confined to Prostate 11 2
Not Confined to Prostate* 4 9 0.02
-----------------------------------------------------------------------------
*Resection margins are positive or extra-prostatic invasion is
present.
Prostatic Tumor Volume
LYCOPENE CONTROL
GROUP GROUP
(N=15) (N=11) p
---------------------------------------------------------------
Volume 4cc< 12 5
Volume >4cc 3 6 0.22
Plasma PSA Level
(mean ng/dl)
LYCOPENE CONTROL
GROUP GROUP
(N=15) (N=11) p
-----------------------------------------------------------------------------
Pre-Intervention 6.89 6.74
Post-Intervention 5.64 7.65
-18% +14% 0.22
---------------------------------------------------------------------------
Extent of Prostatic
Intraepithelial Neoplasia (PIN)
LYCOPENE CONTROL
GROUP GROUP
(N=15) (N=11) p
-----------------------------------------------------------------------------------
Focal 5 0
Multifocal/diffuse 10 11 0.05
-----------------------------------------------------------------------------------
Expression of Biomarkers
In Prostatic Tumor
Lycopene Control
(n=4) (n=4) p
------------------------------------------------------------------------------------
Connexin-43 0.6281 0.2514 0.13
bcl-2 0.5430 0.5056 0.59
bax 1.0531 0.6848 0.33
bax/bcl-2 1.9279 1.4896 0.54
-------------------------------------------------------------------------------------
Expression of Biomarkers
in Benign Prostatic Tissue
Lycopene Control
(n=8) (n=6) P
-------------------------------------------------------------------------------
Lycopene (ng/gm) 0.5284 0.3587 0.02
(n=5) (n=3)
Connexin 43 0.6436 0.5101 0.44
bcl-2 0.6324 0.5765 0.31
bax 0.6218 0.7892 0.28
------------------------------------------------------------------------------------
Conclusions
• Lycopene (Lycomato ®) supplementation
for three weeks is well tolerated by patients
with prostate cancer without any side
effects.
• After three weeks of lycopene
supplementation prostate tissue levels of
lycopene increase associated with
upregulation of gap junctional protein Cx43.
Conclusions
• Clinical markers, including HGPIN and
serum PSA level improve in patients
receiving lycopene supplementation
• Although these results are preliminary other
investigators have obtained similar results
(Bowen et al, JNCI) suggesting activity of
lycopene in patients with prostate cancer.
Soy Isoflavones
CH3 B. Genistein
A. Tamoxifen
O-CH2-CH2-N
CH3 OH
HO O
HO
O
OH
CH3
C. Estradiol (E2)
HO
Soy isoflavones and cancer
• Epidemiologic studies show an inverse
association between dietary soy intake and
cancer risk (breast, prostate, lung, colon,
head and neck and others)
• Genistein and daidzein are the most
abundant isoflavones in soy
• Genistein has activity against a variety of
cancer cells in culture, animal model and
clinical studies
Genistein and Prostate
Cancer
• Inhibits growth and induces apoptosis in Pca cells
• Growth inhibition mediated by G2/M cell cycle arrest
and up-regulation of p21WAF1
• Down-regulates cyclin B1, CDKs, Bcl-2/Bcl-xL
• Up-regulates Bax expression and induces translocation
of Bax to Mitochondria
Genistein
• Down-regulates MMP-2, MMP-9, uPA,
c-IAP and VEGF
• Inactivates Akt and NF-kB (by
inhibiting IKK)
– blocks nuclear translocation of p50 and p65
– inhibits phosphorylation of IkBa
– decreases MEKK1 kinase activity
Growth Factor, Cytokine Genistein
NIK IKK Akt
P
p50 p65 NFkB
P
Active
IkB p50 p65 NFkB
Degradation
Ubiquitin-Proteasome
Nuclear Translocation
p50 p65
kB site •cIAP-1, XIAP, MMP-9,
uPA, VEGF, etc.
Transcription
Effect of Dietary Genistein on MMP Gene
Expression in Experimental Metastasis
Affymetrix Human Genome U95 or U133A Array
Cluster Analysis According to
Biological Function
Numbers of altered genes in different categories in
PC3 bone tumors after genistein treatment
Category Up Down
apoptosis 12 1
cell cycle arrest, negative regulation 13 0
of cell proliferation and transcription
signal transduction, chemotaxis 10 7
regulation of transcription and 11 10
protein biosynthesis
oncogenesis 8 4
Based on Cluster, Onto-Express, and GenMAPP Software
Effects of genistein on gene expression*
*Based on in vitro and in vivo gene profiling with and without genistein
Dietary Genistein and Experimental PC3
Bone Metastasis (Neoplasia 6:354-363, 2004)
p0.0001
p=0.0003
control prevention
SCID-Human Model of Prostate
Cancer Bone Metastasis
1 cm
Normal PC3 LNCaP LUCaP 23.1
Phase II clinical trial of soy isoflavones in
patients with prostate cancer
Study subjects:
• Histologically proven prostate cancer with
PSA progression.
• No other therapy for prostate cancer, except
patients already on LHRH analogue were
required to continue it.
• Patients had to demonstrate a rising trend
with three successive elevations at a
minimum interval of two weeks or at least
two PSA values at least 2 weeks apart with a
minimum PSA of 10 ng/ml.
Treatment
• Soy isoflavone (Novasoy®) 100mg orally
twice daily.
• Treatment duration: Maximum 6 months.
• Treatment compliance: Medication
calendars were completed by study
subjects and remaining pill counts were
done on returned bottles.
Phase II clinical trial of soy isoflavones in
patients with prostate cancer
• Group 1 (n=4)
– previously untreated (watchful waiting)
• Group 2 (n=18)
– PSA-failure, post-surgery or -radiation
• Group 3 (n=19)
– PSA-failure, post-hormone therapy
(hormone refractory)
PSA response
• Group 1
Stable 3/4 patients (75%)
• Group 2
Stable 15/18 patients (83%)
• Group 3
Stable 6/19 patients (32%)
Plot of predicted rise in log PSA with time
6.5
5.5
log PSA
G3
4.5
intervention
3.5
2.5 G2
1.5
0 100 200 300 400 500
Days
Toxicity and compliance
• There was no grade 2 or greater
toxicity. No patients stopped treatment
because of side effects.
• Compliance was excellent with all
subjects taking more than 80% of
prescribed study pills.
Phase II clinical trial of lycopene and
soy isoflavones in prostate cancer
• Lycopene and soy isoflavones have activity
against prostate cancer in cell culture, animal and
clinical studies
• We hypothesized that the combination of
lycopene and soy isoflavones taken together may
be more effective in patients with prostate cancer
• We conducted a clinical trial in patients with PSA
relapse prostate cancer to test the hypothesis
Patient eligibility
• Histologically proven prostate cancer with
PSA progression.
• No other therapy for prostate cancer, except
for the patients who were already on LHRH
analogue were required to continue it.
• Patients had to demonstrate a rising trend
with three successive elevations at a
minimum interval of two weeks or at least
two PSA values at least 2 weeks apart with a
minimum PSA of 10ng/ml.
Treatment
• Lycopene arm: Lycomato ® 15mg orally
twice daily.
• Combination arm: Lycomato ® 15mg +
soy isoflavone (Solgen®) 40mg orally
twice daily.
• Treatment duration: Maximum 6 months.
• Treatment compliance: Patients were
given a medication calendar and pill counts
were done on returned bottles.
Phase II clinical trial of lycopene and soy isoflavones in prostate cancer
Patient Characteristics Lycopene N=38 (53.5%) Lycopene + Soy Isoflavone N=33 (46.5%)
Median Age 73 years 76 years
Range (57-89 years) (50-91 years)
Race
Caucasian 24 (63%) 23 (70%)
African American 12 (31%) 9 (27%)
Other 2 (6%) 1 (3%)
Prior Systemic Therapy
Hormones 14 (36%) 11(33%)
None 24 (64%) 22 (67%)
Presence of metastases
Present 8 (21%) 10 (30%)
Absent 30(79%) 23 (70%)
Median PSA (Range) 6.1ng/ml (1.1-147ng/ml) 6.9ng/ml (0.8-60.9ng/ml)
Vaishampayan U, et al. Nutr Cancer 2007.
Results
• 35 (95%) of 37 patients on lycopene
had PSA stabilization
• 22 (67%) of 33 patients on lycopene +
soy had PSA stabilization.
• In both treatment arms, there was a
decline in the rate of PSA rise in
hormone sensitive (p=0.015) and
hormone refractory (p=0.017) patients.
Phase II clinical trial of lycopene and soy isoflavones in patients with prostate ca.
PSA rise before and after treatment
Hormone Sensitive Patients
7
6
Predicted PSA
5
4
3
2
-400 -300 -200 -100 0 100 200
Days
Solid line is lycopene only arm, and dashed line is lycopene+soy arm
Phase II clinical trial of lycopene and soy isoflavones in patients with prostate ca.
PSA rise before and after treatment
Hormone Refractory Patients
40
30
Predicted PSA
20
10
0
-200 -100 0 100 200
Days
Solid line is lycopene only arm, and dashed line is lycopene+soy arm
Conclusions
• The results of this phase II randomized
clinical trial demonstrate the role of
lycopene in decelerating the rate of PSA rise
in patients with relapsed prostate cancer.
• The results suggest that soy isoflavones in
combination with lycopene may have an
adverse effect on the PSA response to
lycopene.
Lycopene, Soy and Zinc
Prostate Cancer Studies
• Wayne State University, Karmanos Cancer Institute
– O. Kucuk, M. Cher, E. Pontes
– W. Sakr
– F. Sarkar, Y. Li,
– A. Prasad
– Z. Djuric
– M. Banerjee
– G. Hillman, J. Forman
• Michael Pollak (McGill University, Montreal)
• Fred Khachik (University of Maryland)
• M. Baykara, A. Ciftcioglu, G. Yildirim-Kupesiz, F. Koseoglu-Andic
(Akdeniz University, Turkey)
• F. Saatcioglu, B. Lazarevic (Oslo University, Norway)
• H. Mukhtar (University of Wisconsin, Madison, WI)
• D. Doerge (National Center for Toxicology, Jefferson, AK)
Let food be your
medicine.
Hippocrates, 400 BC
