Combined Inhibitory Effects of Green Tea Polyphenols and Selective Cyclooxygenase-2 Inhibitors on the Growth of Human Prostate Cancer Cells Both In vitro and In vivo

Abstract

Purpose: Cyclooxygenase-2 (COX-2) inhibitors hold promise for cancer chemoprevention; however, recent toxicity concerns suggest that new strategies are needed. One approach to overcome this limitation is to use lower doses of COX-2 inhibitors in combination with other established agents with complementary mechanisms. In this study, the effect of (À)epigallocateocatechin-3-gallate (EGCG), a promising chemopreventive agent from green tea, was tested alone and in combination with specific COX-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo. Experimental Design: Human prostate cancer cells LNCaP, PC-3, and CWR22Rr1were treated with EGCG and NS398 alone and in combination, and their effect on growth and apoptosis was evaluated. In vivo, athymic nude mice implanted with androgen-sensitive CWR22Rr1 cells were given green tea polyphenols (0.1% in drinking water) and celecoxib (5 mg/kg, i.p., daily, 5 days per week), alone and in combination, and their effect on tumor growth was evaluated. Results: Combination of EGCG (10-40 Amol/L) and NS-398 (10 Amol/L) resulted in enhanced (a) cell growth inhibition; (b) apoptosis induction; (c) expression of Bax, pro-caspase-6, and pro-caspase-9, and poly(ADP)ribose polymerase cleavage; (d) inhibition of peroxisome proliferator activated receptor g; and (e) inhibition of nuclear factor-nB compared with the additive effects of the two agents alone, suggesting a possible synergism. In vivo, combination treatment with green tea polyphenols and celecoxib resulted in enhanced (a) tumor growth inhibition, (b) lowering of prostate-specific antigen levels, (c) lowering of insulin-like growth factor-I levels, and (d) circulating levels of serum insulin-like growth factor binding protein-3 compared with results of single-agent treatment. Conclusions:These data suggest synergistic and/or additive effects of combinatorial chemopreventive agents and underscore the need for rational design of human clinical trials.

Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis

“…The effect of EGCG (20 and 40 mM) and TRAIL (100 ng ml À1 ) on the viability of cells was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay as described in Adhami et al (2007). The effect of each compound alone and in combination on growth inhibition was assessed as percentage of cell viability in which vehicletreated cells were taken as 100% viable.…”

Dietary agents for chemoprevention of prostate cancer

“…TRAMP mice fed with green tea polyphenols exhibited significant inhibition of IGF-1 and restoration of IGFBP-3 with marked delay in CaP progression [16]. In addition, down-regulation of AR and insulin-like growth factor-1, modulation of inflammation biomarkers, and decrease in the MAPK signaling seen in EGCG treated mice may contribute to the reduction in cell proliferation and induction of apoptosis by EGCG and provide a biochemical basis for suppressing CaP without overt toxicity [17,18]. In addition, testosterone mediated induction of ornithine decarboxylase, an important contributor of CaP development, is inhibited by green tea polyphenols both under in vitro and in vivo situations [19].…”

Quantification of Antioxidants by Using Chlorpromazine Hydrochloride: Application of the Method to Food and Medicinal Plant Samples

“…2 Antioxidants can reduce oxidative damage caused to cells and biomolecules, defend cancer causing agents, and lower the risk of cardiovascular disease, diabetes, and dementia including Alzheimer's disease. 3,4 Free radicals generally play a role in the pathogenesis of chronic degenerative diseases including cancer, autoimmune, inflammatory, cardiovascular, neurodegenerative diseases and aging. Owing to these facts, synthetic and natural compounds with potential antioxidant activity are receiving increased attention in biological research, medicine and pharmacy.…”