Safety and chemopreventive effect of Polyphenon E in preventing early and metastatic progression of prostate cancer in TRAMP mice

Abstract

Prostate cancer treatment is often accompanied by untoward side effects. Therefore, chemoprevention to reduce the risk and inhibit the progression of prostate cancer may be an effective approach to reducing disease burden. We investigated the safety and efficacy of Polyphenon E, a green tea extract, in reducing the progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. A total of 119 male TRAMP and 119 C57BL/6J mice were treated orally with one of 3 doses of Polyphenon E (200, 500, and 1,000 mg/kg/day) in drinking water ad libitum replicating human achievable doses. Baseline assessments were performed before treatments. Safety and efficacy assessments during treatments were performed when mice were 12, 22, and 32 weeks old. The number and size of tumors in treated TRAMP mice were significantly decreased compared with untreated animals. In untreated 32 weeks old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period. Furthermore, Polyphenon E treatment significantly inhibited metastasis in TRAMP mice in a dose-dependent manner (P = 0.0003). Long-term (32 weeks) treatment with Polyphenon E was safe and well tolerated with no evidence of toxicity in C57BL/6J mice. Polyphenon E is an effective chemopreventive agent in preventing the progression of prostate cancer to metastasis in TRAMP mice. Polyphenon E showed no toxicity in these mouse models. Our findings provide additional evidence for the safety and chemopreventive effect of Polyphenon E in preventing metastatic progression of prostate cancer.

Conflict of interest statement

All authors have no conflict of interest, thus no direct or indirect commercial financial incentive associated with this study.

Figures

Figure 1

Contrasting histological appearance of the (A) anterior, (B) dorsal, (C) lateral, and (D) ventral lobes of the prostate gland from 32 week old C57BL/6J mice administered high dose treatment of 1000 mg Polyphenon E/kg body weight/day throughout life beginning at 7 weeks of age, and corresponding prostate lobes of age-matched TRAMP mice (E-L) administered the same life-long high dose of Polyphenon E. Prostates of high dose Polyphenon E treated C57BL/6J mice were without significant lesions (A-D), while prostates of high dose Polyphenon E treated 32 week old TRAMP mice developed either epithelial hyperplasia (E-H) or adenoma (I-L), which did not progress to metastatic carcinoma as frequently as untreated TRAMP control mice.

Figure 2

A. Proportion of mice with metastasis: Polyphenon E treatment at low (200 mg/kg/day), medium (500 mg/kg/day), and high (1000 mg/kg/day) doses reduced metastasis. Controls were administered drinking water with no Polyphenon E. Metastasis inhibition by Polyphenon E treatment showed a dose-dependent response (P=0.0003). B. Incidence of hyperplasia, adenoma, and high grade carcinoma in 32 week old TRAMP mice administered low, medium, and high doses of Polyphenon E or tap water (control) (*P<0.05 compared to controls that developed carcinoma). C. Mean distribution-adjusted lesion grade of total and different lobes (anterior, dorsal, lateral and ventral) of the prostate in control TRAMP mice and mice treated with low, medium and high Polyphenon E.

Figure 3

Metastatic prostate adenocarcinoma was abrogated by high dose Polyphenon E consumption, but developed invariably in all 32 week old untreated control TRAMP mice provided drinking water without Polyphenon E treatment (A-I). PCa of TRAMP mice presented as either an expansile mass of proliferating cells that invaded beyond the acinus basement membrane into the interstitium (A, arrow), as a cribriform, papillary, tubular mass of well differentiated epithelial cells with supporting stroma that expanded well beyond the acinus capsule and effaced normal glandular structures (B), or as a sheet of pleomorphic epithelial cells that invaded and surrounded glandular acini (C). PCa of vehicle-treated control TRAMP mice were often comprised of anaplastic, pleomorphic cells (D, E), with one or multiple metastases to distant foci, including the lymph node (F), lung (G), kidney (H), or liver (I).

Figure 4

Demonstration of MRI (A), US (B) and gross pathology (C) of prostate tumors in the 32 week group of TRAMP mice. In the MRI, white arrows point to the prostate/seminal vesicles and black arrows point to the bladder for reference. In the US images, white arrows point to prostate tumor. 1, Control; 2, Low; 3, Medium; 4, High