The chemopreventive activity of green tea (GT) is limited by the low bioavailability and extensive methylation of GT polyphenols (GTPs) in vivo. We determined whether a methylation inhibitor quercetin (Q) will enhance the chemoprevention of prostate cancer in vivo. Androgen-sensitive LAPC-4 prostate cancer cells were injected subcutaneously into severe combined immunodeficiency (SCID) mice one week before the intervention. The concentration of GTPs in brewed tea administered as drinking water was 0.07% and Q was supplemented in diet at 0.2% or 0.4%. After 6-weeks of intervention tumor growth was inhibited by 3% (0.2% Q), 15% (0.4% Q), 21% (GT), 28% (GT+0.2% Q) and 45% (GT+0.4% Q) compared to control. The concentration of non-methylated GTPs was significantly increased in tumor tissue with GT+0.4% Q treatment compared to GT alone, and was associated with a decreased protein expression of catechol-O-methyltransferase and multidrug resistance-associated protein (MRP)-1. The combination treatment was also associated with a significant increase in the inhibition of proliferation, androgen receptor and phosphatidylinositol 3-kinase/Akt signaling, and stimulation of apoptosis. The combined effect of GT+0.4% Q on tumor inhibition was further confirmed in another experiment where the intervention started prior to tumor inoculation. These results provide a novel regimen by combining GT and Q to improve chemoprevention in a non-toxic manner and warrant future studies in humans.
Keywords: 4″-MeEGCG; 4″-O-methyl EGCG; AR; COMT; Catechol-O-methyltransferase; EC, (−)-epicatechin; ECG, (−)-epicatechin-3-gallate; EGC; EGCG, (−); GT; GTPs; Green tea; HD; HPLC; LD; MRP; PI3K; PSA; Prostate cancer; Q; Quercetin; SCID; SCID mice; androgen receptor; catechol-O-methyltransferase; epigallocatechin; epigallocatechin-3-gallate; green tea; green tea polyphenols; high dose; high-performance liquid chromatography; low dose; mTOR; mammalian target of rapamycin; multidrug resistance-associated protein; phosphatidylinositol 3-kinases; prostate-specific antigen; quercetin; severe combined immunodeficiency.