Abstract 607: Enhanced inhibition of prostate cancer xenograft tumor growth by combining quercetin and green tea

Abstract

Abstract The chemopreventive activity of green tea (GT) and green tea polyphenols (GTPs) in prostate cancer has been demonstrated in preclinical cell culture and animal models. However, extensive methylation of GTPs in vivo to less active methyl-metabolites may be limiting the anti-cancer activity of GT. The objective of the present study was to investigate whether quercetin (Q), a natural inhibitor of catechol-O-methyltransferase (COMT), will increase tissue concentrations of non-methylated GTPs and enhance the inhibition of xenograft tumor growth in severe combined immune deficient (SCID) mice. Androgen-sensitive LAPC-4 prostate cancer cells were injected subcutaneously into SCID mice (n=12 per group). SCID mice were randomly assigned to four groups: control, GT, Q, and GT + Q treatment. The interventions were initiated when tumors reached volume of 10mm3. The final concentration of GTPs in brewed tea administered as drinking water was 0.07% and Q was supplemented in AIN-93G diet at a concentration of 4g/kg diet. There were no differences in food intake, body weight or water consumption during the intervention. Tissue bioavailability of GTPs was increased significantly by 2 to 3-fold in lung, kidney and xenograft tumors and showed a trend to increase by 1.3-fold in liver tissue by GT and Q treatment compared to GT alone. Methylation of epigallocatechin gallate (EGCG), the main polyphenol in green tea, was decreased in tissues from mice in the GT+Q group. After 6 weeks, tumor growth was inhibited by 16% (Q alone), 21% (GT alone), and 45% (GT+Q) compared to the control group. Western blot analysis demonstrated a significant inhibition of methyl transferases such as COMT (31%) and DNA methyltransferase (DNMT) (52%) in tumors from the GT+Q group compared to the control. It has been demonstrated previously that EGCG can act as androgen receptor (AR) antagonist as well as inhibit angiogenesis via inhibition of the vascular endothelial growth factor (VEGF). Together Q+GT inhibited protein expression of AR (35%), prostate-specific antigen (PSA) (39%), and VEGF (25%) more than either GT or Q alone. This study demonstrates an enhanced inhibition of prostate tumor growth when GT and Q are co-administered and this is likely due to inhibition of methylation resulting in enhanced anti-tumor activity of EGCG via effects on angiogenesis, and androgen-mediated tumor growth. This study sets the stage for future human interventions to confirm the increase in bioavailability and chemoprevention using GT in combination with Q. This project was supported by DOD grant W81XWH-10-1-0298 and NIH grant RO3 CA150047-01. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 607. doi:1538-7445.AM2012-607