stilbenes and Prostatic-Neoplasms--Castration-Resistant

Mediterranean diet may play a role in the prevention of prostate cancer (PCa) development and progression. Cyclooxygenase-2 (COX-2) expression is associated with increased cellular proliferation, prevents apoptosis and favors tumor invasion. We intend to clarify whether resveratrol and other polyphenols effectively inhibit COX-2 activity and induce apoptosis in hormone-resistant PC-3 cell line.. PC-3 cells were cultured and treated with different concentrations of gallic acid, tannic acid, quercetin, and resveratrol in presence of phorbol myristate acetate (PMA; 50 μg/ml) that induces COX-2 expression. Total RNA was extracted and COX-2 expression was analyzed by relative quantification real-time PCR (ΔΔCt method). COX-2 activity was determined by PGE-2 detection using ELISA. Caspase 3/7 luminescence assay was used to disclose apoptosis. Transitory transfection with short human COX-2 (phPES2 -327/+59) and p5xNF-kβ-Luc plasmids determined COX-2 promoter activity and specifically that dependant of NF-kβ.. COX-2 expression was not modified in media devoid of PMA. However, under PMA induction tannic acid (2.08 ±.21), gallic acid (2.46 ±.16), quercetin (1.78 ±.14) and resveratrol (1.15 ±.16) significantly inhibited COX-2 mRNA with respect to control (3.14 ±.07), what means a 34%, 23%, 46% and 61% reduction, respectively. The inhibition in the levels of PGE-2 followed a similar pattern. All compounds studied induced apoptosis at 48 h, although at a different rate. PMA caused a rise in activity 7.4 ±.23 times phPES2 -327/+59 and 2.0 ±.1 times p5xNF-kβ-Luc at 6h compared to basal. Resveratrol suppressed these effects 17.1 ±.21 and 32.4 ±.18 times, respectively. Similarly, but to a lesser extent, the rest of evaluated polyphenols diminished PMA inductor effect on the activity of both promoters.. Polyphenols inhibit transcriptional activity of COX-2 promoter mediated by NF-kβ. This effect could explain, at least in part, the induction of apoptosis in vitro by these substances in castration resistant PCa.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Screening Assays, Antitumor; Humans; Male; NF-kappa B; Polyphenols; Promoter Regions, Genetic; Prostatic Neoplasms, Castration-Resistant; Resveratrol; Stilbenes; Transcriptional Activation; Wine

Androgen-dependent prostate cancer inevitably progresses to incurable castration-resistant prostate cancer (CRPC) after androgen deprivation therapy. Because castration-induced hypoxia-inducible factor (HIF)-1α enhances the transcriptional activity of androgen receptor (AR) at low androgen levels mimicking the castration-resistant stage, HIF-1α is expected to be a promising target for suppression of growth of CRPC. We investigated the effect of resveratrol (3,4',5-trihydroxy-trans-stilbene) on the growth of human prostate cancer LNCaP xenografts in castrated male BALB/cSlc-nu/nu mice (5 wk old). The mice were administered a control diet or a resveratrol diet (4 g/kg diet) for 40 d. The resveratrol diet significantly suppressed tumor growth compared to the control diet. In LNCaP xenografts, dietary resveratrol decreased the protein level of HIF-1α, but not the AR coactivator β-catenin, and reduced the mRNA levels of androgen-responsive genes. In the control group, β-catenin was predominantly localized in the nucleus with HIF-1α in LNCaP xenografts, whereas dietary resveratrol inhibited the nuclear accumulation of β-catenin. In hypoxic LNCaP cells at a low androgen level mimicking the castration-resistant stage, hypoxia-induced nuclear accumulation of β-catenin was inhibited by resveratrol. Furthermore, resveratrol repressed the expression level of HIF-1α even in the presence of a proteasome inhibitor and suppressed hypoxia-enhanced AR transactivation. These results indicate that dietary resveratrol represses nuclear localization of β-catenin by decreasing the HIF-1α expression, perhaps in a proteasome-independent manner, and inhibits β-catenin-mediated AR signaling; this contributes to suppression of tumor growth of CRPC.

Topics: Animals; Antineoplastic Agents, Phytogenic; beta Catenin; Cell Line, Tumor; Cell Nucleus; Diet; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mice, Inbred BALB C; Mice, Nude; Phytotherapy; Plant Extracts; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Resveratrol; RNA, Messenger; Signal Transduction; Stilbenes; Transcriptional Activation; Vitis