Introduction

Controversy exists on dietary supplements ability to prevent prostate cancer (PCa).

We assessed clinical and molecular activity of a combination of selenium (Se), lycopene and green tea
catechins (GTC), administered at the maximum non-toxic dose, in men with ASAP and/or multifocal
HGPIN.
Patients and methods
Randomised double blind controlled trial included 60 men with ASAP and/or multifocal HGPIN receiving
daily lycopene 35mg, Se 55g and GTC 600mg or placebo for 6 months. Primary end-point was to evaluate
differences of incidence of PCa in the two arms, at rebiopsy. Upon confirmation of plasma lycopene
concentrations falling within 1.2-90mcg/l and no side-effects during phase I (n=10), study proceeded to
phase II (n=50). Clinical and pathological characteristics were recorded including PSA, IPSS and PR25
questionnaires at baseline and end of treatment, when a minimum 12 cores biopsy was scheduled. After
unblinding of pathological results, 8 men (4 placebo and 4 active treatment, 2 with no evidence of disease
and 2 with diagnosis of PCa within each arm respectively) were selected and total RNA extracted from
normal tissue areas. MicroRNA profiling was carried out with the Agilent platform. Raw data were processed
using R statistical language, linear models for microarray analysis and 2-factor ANOVA. Hierarchical
clustering on differentially expressed miRNAs was performed with TMev software.
Results
At 6 months 53 men underwent re-biopsy and 24.5% (n=13) had PCa: 77% of them (n=10) were in the
supplementation group whereas 3 were in the placebo group (p=0.053).Table 1 reports clinico-pathological
variables changes in the 2 arms before and after treatment. No significant variations in PSA, IPSS and PR25
questionnaires were observed. At a mean total follow up of 37 months 3 more PCa were found (all placebos).
A consistent group of microRNAs, overexpressed in PCa and present in progression from HGPIN to
metastasis, were upregulated in the supplementation group only on rebiopsy. In the same group, some
microRNA suppressing the proliferation, invasion, and migration of PCa as well as one underexpressed in
PCa vs non-cancer stroma were downregulated. 31 microRNAs were differently modulated on re-biopsy in
patients who progressed, with a stronger effect in the supplementation group. Amongst them were
oncosuppressors miR-203b-5p and miR-7-2-3p (downregulated) and oncomiR miR-18a-3p (upregulated).
Discussion and Conclusions
High dose combination of lycopene, GTC and Se administered in men harbouring HGPIN and/or ASAP was
associated with a higher incidence of PCa at rebiopsy and overexpression of microRNA implicated in PCa
progression.