FTY720, a fungus metabolite, inhibits in vivo growth of androgen‐independent prostate cancer

• Published in: International journal of cancer Vol. 117; no. 6; pp. 1039 - 1048
• Main Authors: Chua, Chee‐Wai, Lee, Davy Tak‐Wing, Ling, Ming‐Tat, Zhou, Chun, Man, Kwan, Ho, Joanna, Chan, Franky L., Wang, Xianghong, Wong, Yong‐Chuan
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 20.12.2005; Wiley-Liss
• Subjects: Androgens - pharmacology; angiogenesis; Animals; Antineoplastic agents; apoptosis; Apoptosis - drug effects; beta Catenin - analysis; Biological and medical sciences; Body Weight; Cadherins - analysis; Caspase 3; Caspases - analysis; Cell Division - drug effects; Chemotherapy; Fingolimod Hydrochloride; FTY720; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Male; Medical sciences; Mice; Mice, Nude; Neoplasm Metastasis - prevention & control; Neoplasm Transplantation; Neovascularization, Pathologic - prevention & control; Orchiectomy; Pharmacology. Drug treatments; Platelet Endothelial Cell Adhesion Molecule-1 - analysis; proliferation; Propylene Glycols - administration & dosage; Propylene Glycols - toxicity; prostate cancer; Prostate-Specific Antigen - blood; Prostatic Neoplasms - chemistry; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-bcl-2 - analysis; Sphingosine - analogs & derivatives; Tumors; Vascular Endothelial Growth Factor A - analysis; Antineoplastic agent; Cell proliferation; Prostate disease; Metabolite; Fungi; Cancerology; Hormonoindependence; Established cell line; Antiangiogenic agent; Male genital diseases; Thallophyta; Human; Urinary system disease; Androgen; proliferation; Pharmacognosy; angiogenesis; Rodentia; Malignant tumor; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Cell death; Animal; FTY720; Plant origin; Inhibitor; Sex steroid hormone; Prostate cancer; Apoptosis
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.21243

FTY720, a derivative of fungus, has demonstrated dramatic anticancer effect in several malignancies recently. Our study evaluates the therapeutic potential of FTY720 in the treatment of androgen‐independent prostate cancer using a human prostate cancer xenograft in nude mice. CWR22R, an androgen‐independent human prostate tumor xenograft was inoculated into castrated nude mice and the animals were administrated with either normal saline or FTY720 (10 mg/kg) through intraperitoneal (i.p.) injection for 20 days. Body weight and tumor volume were recorded every 2 days, and serum prostate specific antigen (PSA) levels were also measured before and after the treatment. The effect of FTY720 on tumor cell proliferation was examined using antibodies against PCNA and Ki‐67 by immunohistochemical staining, MTT assay and colony forming assay, whereas apoptotic effect of FTY720 was evaluated by TUNEL assay and immunostaining using antibodies against cleaved caspase 3 and Bcl‐2. In addition, the potential inhibitory effect of FTY720 on prostate cancer angiogenesis and metastasis was investigated by immunostaining of CD31, VEGF, E‐cadherin and β‐catenin. Our results showed that FTY720 treatment led to suppression of CWR22R tumor growth without causing any detectable side effects in nude mice. The FTY720‐induced tumor suppression was correlated with decreased serum PSA level as well as reduced proliferation rate, suppression of angiogenic factors, and restoration of E‐cadherin and β‐catenin expression. In addition, the FTY720‐treated tumors showed increased apoptosis rate demonstrated by increased TUNEL‐ and cleaved caspase 3‐positive cells, and decreased Bcl‐2 expression. Our results suggest a potential novel agent in the suppression of androgen‐independent prostate cancer. © 2005 Wiley‐Liss, Inc.