Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenolsSanjay Gupta,* Kedar Hastak,* Nihal Ahmad,* Jonathan S. Lewin,† and Hasan Mukhtar*‡
Departments of *Dermatology and †Radiology, Case Western Reserve University & The Research Institute of University Hospitals of Cleveland, Cleveland, OH 44106
‡To whom reprint requests should be addressed. E-mail:
hxm4@po.cwru.edu.
Communicated by Allan H. Conney, Rutgers, The State University of New Jersey New Brunswick, Piscataway, NJ
Received December 19, 2000; Accepted June 27, 2001.
Development of effective chemopreventive agents against prostate cancer (CaP) for humans requires conclusive evidence of their efficacy in animal models that closely emulates human disease. The autochthonous
transgenic
adenocarcinoma of the
mouse
prostate (TRAMP) model, which spontaneously develops metastatic CaP, is one such model that mimics progressive forms of human disease. Employing male TRAMP mice, we show that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to six cups of green tea per day) significantly inhibits CaP development and increases survival in these mice. In two separate experiments, the cumulative incidence of palpable tumors at 32 weeks of age in 20 untreated mice was 100% (20 of 20). In these mice, 95% (19 of 20), 65% (13 of 20), 40% (8 of 20), and 25% (5 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, liver, and bone, respectively. However, 0.1% GTP (wt/vol) provided as the sole source of drinking fluid to TRAMP mice from 8 to 32 weeks of age resulted in (
i) significant delay in primary tumor incidence and tumor burden as assessed sequentially by MRI, (
ii) significant decrease in prostate (64%) and genitourinary (GU) (72%) weight, (
iii) significant inhibition in serum insulin-like growth factor-I and restoration of insulin-like growth factor binding protein-3 levels, and (
iv) marked reduction in the protein expression of proliferating cell nuclear antigen (PCNA) in the prostate compared with water-fed TRAMP mice. The striking observation of this study was that GTP infusion resulted in almost complete inhibition of distant site metastases. Furthermore, GTP consumption caused significant apoptosis of CaP cells, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of prostate cancer development, progression, and metastasis of CaP to distant organ sites.
