FTY720, a fungus metabolite, inhibits in vivo growth of androgen-independent prostate cancer.
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 beta-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 beta-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.
Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Chee-Wai
CW
Chua
Davy Tak-Wing
DT
Lee
Ming-Tat
MT
Ling
Chun
C
Zhou
Kwan
K
Man
Joanna
J
Ho
Franky L
FL
Chan
Xianghong
X
Wang
Yong-Chuan
YC
Wong
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight; D015820:Cadherins / Q000032:analysis; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009919:Orchiectomy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011409:Propylene Glycols / Q000008:administration & dosage* / Q000633:toxicity; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013110:Sphingosine / Q000031:analogs & derivatives; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D051176:beta Catenin / Q000032:analysis
D000728:Androgens; D015820:Cadherins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011409:Propylene Glycols; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D017430:Prostate-Specific Antigen; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine