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Lycopene Tomato in Prostate Health
Lycopene Tomato in Prostate Health
http://www.elsevier.com/locate/bba
Review
Received 15 September 2004; received in revised form 27 January 2005; accepted 4 February 2005
Available online 13 March 2005
Abstract
Epidemiological evidence associating the decreased risk of prostate cancer with frequent consumption of tomato products inspired us to
conduct a small intervention trial among patients diagnosed with prostate adenocarcinoma. Tomato sauce pasta was consumed daily for 3
weeks before their scheduled prostatectomy, and biomarkers of tomato intake, prostate cancer progression and oxidative DNA damage were
followed in blood and the available prostate tissue. The whole food intervention was so well accepted by the subjects that the blood lycopene
(the primary carotenoid in tomatoes responsible for their red color) doubled and the prostate lycopene concentration tripled during this short
period. Oxidative DNA damage in leukocytes and prostate tissues was significantly diminished, the latter mainly in the tumor cell nuclei,
possibly due to the antioxidant properties of lycopene. Quite surprising was the decrease in blood prostate-specific antigen, which was
explained by the increase in apoptotic death of prostate cells, especially in carcinoma regions. Prostate cancer cell cultures (LNCaP) were also
sensitive to lycopene in growth medium, which caused an increased apoptosis and arrested the cell cycle. A possible explanation of these
promising results may reside in lycopene effects on the genes governing the androgen stimulation of prostate growth, cytokines and on the
enzymes producing reactive oxygen species, all of which were recently discovered by nutrigenomic techniques. Other phytochemicals in
tomato may act in synergy with lycopene to potentiate protective effects and to help in the maintenance of prostate health.
D 2005 Elsevier B.V. All rights reserved.
The prostate, a major male accessory gland, is a tence. These perspectives cause many doctors and patients
potential source of serious disorders affecting health and to accept a bwatchful waitingQ strategy, since cancers of the
the quality of life in older men. The walnut-size gland prostate are relatively slow growing, especially in older
envelops the urethra just below the bladder, and several men.
pathological conditions have a tendency to obstruct the Prostate cancer is a worldwide health problem, most
flow of urine which may damage the bladder and kidneys. common in northwestern Europe (Scandinavian countries)
Prostate disorders include inflammation (prostatitis), and North America, but rare in East Asia (China, Japan). An
benign prostatic hyperplasia (BPH) and prostate cancer. estimated 230,000 new cases will occur in the US in 2004,
While acute or chronic prostatitis may afflict any adult with 30,000 deaths in the same year, placing prostate cancer
male, by the age of 70 years, more than 40% of men as the second leading cause of cancer death in US men [1].
develop an enlargement of prostate due to BPH, and by the Incidence rates are the highest in African American men and
age of 80 years, most will have prostate cancer. The Caribbean men of African descent. Besides age, ethnic
treatment for cancer may involve radiation, various origin, and family history (genetic predisposition), the risk
surgical procedures, anti-androgen hormonal therapy, with factors for prostate cancer include smoking, high intake of
possible side effects of urinary incontinence and impo- fat, obesity and lack of exercise [2]. Therefore the
prevention of prostate diseases is one of the pressing health
issues in the developed countries. An exploration of many
T Corresponding author. Tel.: +1 312 996 1210; fax: +1 312 413 0319. lifestyle factors, including dietary compounds and their
E-mail address: [email protected] (M. Stacewicz-Sapuntzakis). mechanism of action, is underway through epidemiological
0925-4439/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbadis.2005.02.004
M. Stacewicz-Sapuntzakis, P.E. Bowen / Biochimica et Biophysica Acta 1740 (2005) 202–205 203
sections from our subjects, both in hyperplastic and tumor tissue, after 18 days of tumor growth. The gene chip
neoplastic cells. The apoptotic index (AI) of cancer areas analysis of tumor tissue revealed that lycopene supplemen-
more than tripled during the supplementation interval, from tation upregulated 101 genes and suppressed 261 genes. The
0.8% to 2.7%. A comparable group of patients, who did not most significant was the decrease of steroid 5-a-reductase
consume tomato sauce dishes, had 1.9% AI in their expression, because of the role of 5-a-dihydrotestosterone
prostatectomy specimens [11]. Hyperplastic areas seemed (DHT) in prostate cancer development [17]. DHT blocks
to double their AI during the intervention (from 0.7% to LNCaP apoptosis in cell cultures [18], which could explain
1.4%), but a similar result (1.4%) was obtained from the the effect of lycopene on apoptosis in the same cell strain in
prostatectomy tissue of patients who did not consume our our study. A whole set of androgen target genes was
tomato sauce dishes. Great variability in the distribution of significantly downregulated in the lycopene-treated group,
apoptotic cells for BPH and cancer areas was found in both as well as those for two cytokines, insulin-like growth factor
biopsy and resected prostate tissues, but in five of our I (IGF-I) and interleukin-6 (IL-6), both implicated in
subjects among the 26 examined, the AI ranged as high as prostate cancer development [19,20]. Two important
4.7%–13.3% for the most apoptotic cell areas after tomato enzymes generating reactive oxygen species (ROS)
sauce supplementation. Thus, it is possible that tomato exhibited decreased expression, the inducible nitric oxide
sauce intake may induce apoptosis in some tumor cells and synthase and NADPH oxidase. Similar supplementation of
arrest cancer progression. young healthy rats with lycopene for 8 weeks resulted in a
Which of the many phytochemicals in tomatoes could be significant accumulation of lycopene in prostate, with an
responsible for the observed apoptotic effects? We turned to accompanying reduction in the gene expression of inflam-
cell culture studies of human prostate cancer LNCaP to matory signaling (cytokines, immunoglobulins and their
investigate the cell cycle, viability and apoptosis in the receptors), IGF-I, and decreased androgen activation.
presence and absence of lycopene in the growth medium Lycopene did not interfere with normal prostate growth
[12]. Water soluble 10% lycopene beadlets were used as a but seemed to modulate the expression of genes crucial to
source of lycopene against placebo beadlets of matched prostate health. These findings should be confirmed by
composition. Four levels of lycopene in the culture medium using the same techniques to investigate gene regulation in
were investigated (0.1, 0.5, 1, and 5 AM), which correspond prostate cancer tissue of human subjects, with concurrent
to 0.1, 0.5, 1 and 5 nmol/mL, to encompass the average measurement of androgens and lycopene concentrations in
lycopene concentration in the serum of our subjects (1.26 prostate and plasma.
AM) and in prostate tissue (0.82 nmol/g) after tomato sauce A small clinical trial of lycopene supplementation (30
intervention. Lycopene was absorbed by LNCaP cells mg/day, tomato oleoresin extract) was conducted on 15
during the first 24 h and significantly inhibited their growth prostate cancer patients, who were compared with 11
at each dose level. Flow cytometry indicated significant cell unsupplemented cases [21]. The results were mostly
cycle arrest at a physiologically feasible 1 AM dose. The inconclusive, because the plasma lycopene levels of
incidence of apoptosis increased with time in a dose- supplemented patients did not increase significantly after 3
dependent manner, reaching 20.6% at the highest 5 AM weeks of treatment. However, the researchers noticed a
concentration. Similar effects were obtained by other relative decrease in the extension of prostate cancer to
researchers with various lines of human prostate cancer surgical margins and extra-prostatic tissues, as well as in the
cells (PC-3, DU 145) incubated with 5 AM lycopene [13]. extent of high-grade prostatic intraepithelial neoplasia
These results are consistent with the data from our subjects (PIN). There is also a startling case report of a patient with
and support the role of lycopene as a possible bioactive metastatic prostate cancer, whose formal treatment, includ-
compound in tomatoes, preventing and controlling the ing prostatectomy, was unsuccessful [22]. He entered
development of prostate cancer [14]. hospice care and began treating himself with lycopene (10
The observed multiple effects of lycopene in prostate mg/day) and saw palmetto (900 mg/day) supplements. His
physiology demand a specific action on the molecular level PSA decreased from 365 ng/mL to 8 mg/mL within 2
of gene expression to explain the mechanism of cell months, stabilizing at 3–8 ng/mL, his bone metastases
proliferation arrest, apoptosis and the decrease in oxidative improved and he was asymptomatic after 18 months of this
stress. Strong support for the bioactive properties of self-administered supplementation.
lycopene in prostate health was recently found in animal Although lycopene appears to be a bioactive compound
studies [15,16]. When MatLyLu Dunning prostatic adeno- in cell culture and animal studies, we cannot exclude the
carcinoma cells are injected into the ventral prostate of possibility of a synergistic action with other phytochemicals
Copenhagen rats, they quickly develop into lethal tumors. in tomato, especially glycoalkaloids (tomatine), phenolic
Although laboratory rats absorb lycopene very poorly compounds (quercetin, kaempferol, naringenin, and chloro-
compared to humans, sufficient amounts (200 mg lyco- genic acid), salicylates, and carotenoids other than lycopene
pene/kg diet) were incorporated in their diet during the 4 (phytoene and phytofluene). Salicylates are well known for
weeks before tumor cell injection to produce a 1 AM their anti-inflammatory action, and quercetin inhibits the
lycopene concentration in plasma, and 0.4 nmol/g in the prostate androgen receptor [23]. Boileau et al. [24] found a
M. Stacewicz-Sapuntzakis, P.E. Bowen / Biochimica et Biophysica Acta 1740 (2005) 202–205 205
much greater effect of whole tomato powder diet on rat mulation and modulation of biomarkers of carcinogenesis, Exp. Biol.
prostate cancer, induced with N-methyl-N-nitroso-urea and Med. 227 (2002) 886 – 893.
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