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.
OBJECTIVE
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 (-)epigallocatechin-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.


METHODS
Human prostate cancer cells LNCaP, PC-3, and CWR22Rnu1 were 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 CWR22Rnu1 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 micromol/L) and NS-398 (10 micromol/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 gamma; and (e) inhibition of nuclear factor-kappaB 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.
Adhami
Vaqar Mustafa
VM
Department of Dermatology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
Malik
Arshi
A
Zaman
Najia
N
Sarfaraz
Sami
S
Siddiqui
Imtiaz Ahmad
IA
Syed
Deeba Nadeem
DN
Afaq
Farrukh
F
Pasha
Farrukh Sierre
FS
Saleem
Mohammad
M
Mukhtar
Hasan
H
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001628:Beverages; D015153:Blotting, Western; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009578:Nitrobenzenes / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology*; D059808:Polyphenols; D011471:Prostatic Neoplasms / Q000517:prevention & control*; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013662:Tea / Q000737:chemistry*
D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D005419:Flavonoids; D009578:Nitrobenzenes; D010636:Phenols; D059808:Polyphenols; D011720:Pyrazoles; D013449:Sulfonamides; D013662:Tea; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000068579:Celecoxib