Cancer Therapy: Preclinical Herbal Extract of Wedelia chinensis Attenuates Androgen Receptor Activity and Orthotopic Growth of Prostate Cancer in Nude Mice

Purpose: Wedelia chinensis is a common ingredient of anti-inflammatory herbal medicines in Taiwan and southern China. Inflammation is involved in promoting tumor growth, invasion, and metastasis. This study aims to test the biological effects in vivo of W. chinensis extract on prostate cancer. Experimental Design: The in vivo efficacy and mechanisms of action of oral administration of a standardized extract of W. chinensis were analyzed in animals bearing a subcutaneous or orthotopic prostate cancer xenograft. Results: Exposure of prostate cancer cells to W. chinensis extract induced apoptosis selectively in androgen receptor (AR)–positive prostate cancer cells and shifted the proportion in each phase of cell cycle toward G2-M phase in AR-negative prostate cancer cells. Oral herbal extract (4 or 40 mg/kg/d for 24-28 days) attenuated the growth of prostate tumors in nude mice implanted at both subcutaneous (31% and 44%, respectively) and orthotopic (49% and 49%, respectively) sites. The tumor suppression effects were associated with increased apoptosis and lower proliferation in tumor cells as well as reduced tumor angiogenesis. The antitumor effect of W. chinensis extract was correlated with accumulation of the principle active compounds wedelolactone, luteolin, and apigenin in vivo. Conclusion: Anticancer action of W. chinensis extract was due to three active compounds that inhibit the AR signaling pathway. Oral administration of W. chinensis extract impeded prostate cancer tumorigenesis. Future studies of W. chinensis for chemoprevention or complementary medicine against prostate cancer in humans are thus warranted. (Clin Cancer Res 2009;15(17):5435–44) Carcinoma of the prostate gland is the most common malignancy in males in the western world (1). Despite the low incidence of prostate cancer in oriental countries, statistics from Taiwan reveal prostate cancer deaths have continued to increase in the past two decades. Androgen ablation therapy remains the most effective means of treating metastatic prostate cancer tumors (2, 3). This therapy often induces apoptosis in the majority of prostate cancer cells by blocking testosterone signaling at the androgen receptor (AR) and lowering the expression of AR-regulated genes including prostate-specific antigen (PSA), a serologic biomarker up-regulated by androgens (4, 5). The CWR22 tumor model, based on implantation of a human prostate cancer in an athymic nude mouse, progresses in the same androgen-dependent manner as observed in clinical prostate cancer tumors. Further development from castrationrelapsed CWR22 tumors created subline tumors and a cell line, 22Rv1, which retain expression of AR and show androgen sti‐ mulation of neoplasia (6, 7). Earlier, we devised the androgeninduced PSA-luciferase activity in prostate cancer 22Rv1 cells and a derived stable clone, 103E, as a cell-based assay to detect any AR modulator effect of herbal extract or compounds (8–10). To determine whether herbal remedies or compounds can inhibit prostate cancer growth in orthotopic sites, we constructed a tumor model by orthotopic implantation of luciferase-expressing 103E cells into nude mice to serially image prostate cancer growth. The present study used this bioluminescent tumor model to assess the preventive and therapeutic effects of a standardized herbal extract against prostate cancer. Authors' Affiliations: Agricultural Biotechnology Research Center and Institute of Biochemistry, Academia Sinica; Institute of Biochemical Sciences, National Taiwan University; Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Received 2/6/09; revised 5/25/09; accepted 5/27/09; published OnlineFirst