Control of prostate cell growth, DNA damage and repair and gene expression by resveratrol analogues, in vitro

The chemopreventive potential of resveratrol is marred by its low bioavailability. Studies of modified resveratrol may reveal features that affect its bioefficacy and bioavailability. We compared the anti-proliferative and gene regulatory activities of resveratrol with trimethoxy-resveratrol and triacetyl-resveratrol using cultured human prostate cancer (CaP) cells. LNCaP cells were incubated with resveratrol and its analogues. Changes in proliferation, colony formation, cell cycle, apoptosis and prostate specific antigen (PSA) PSA were determined. DNA damage was assayed by phosphorylated-histone H2AX changes. Expression of total and serine-15-phosphorylated p53 and p53-inducible cell cycle regulatory protein p21 and ribonucleotide reductase subunit p53R2 involved in DNA repair were measured by immunobloting and reverse transcription-polymerase chain reaction. Exposure to resveratrol or triacetyl-resveratrol activated p53, increased p21 and p53R2 and decreased PSA expression in LNCaP cells. These changes were attenuated by the p53 inhibitor pifithrin-alpha. However, LNCaP cells exposed to trimethoxy-resveratrol showed induction of apoptosis, reduction in G(1) and prolongation of the SG(2)M phases. Resveratrol and analogues were also studied in CWR22Rv1 (containing mutated p53) and p53-null PC-3 cells. CWR22Rv1 cells exposed to resveratrol and triacetyl-resveratrol showed a G(1)S block, concomitant with increased p53 and p21 expression; however, identically treated PC-3 cells showed attenuated progression through the SG(2)M phases. Trimethoxy-resveratrol did not affect CWR22Rv1 cell cycle but reduced and expanded PC-3 cells in the G(1) and SG(2)M phases, respectively. These results suggest that triacetyl-resveratrol and trimethoxy-resveratrol are active against different stage CaP cells, using overlapping and distinct mechanisms.