Inhibition of growth and induction of TGF-beta 1 in human hepatocellular carcinoma with androgen receptor by cyproterone acetate in male nude mice.
OBJECTIVE
Hepatocellular carcinoma possesses androgen receptor but its true role is not known. This study aimed to investigate the effect of an anti-androgen cyproterone acetate on the growth of androgen receptor-positive hepatocellular carcinoma.


METHODS
Androgen receptor-positive human hepatocellular carcinoma cells (KYN-1/SM-10) were subcutaneously transplanted into male nude mice. When the tumor size was about 10 mm, animals were subcutaneously administered cyproterone acetate (0.1 mg/day and 0.8 mg/day) or solvent alone for 21 days. Animals were serially sacrificed for measurements of testicular weight, tumor size, and cytosolic and nuclear androgen receptor levels in tumor. Proliferating cell nuclear antigen, transforming growth factor-alpha, and transforming growth factor-beta 1 in tumor were investigated immunohistochemically, using monoclonal antibodies. Apoptotic activity was also studied by the in situ DNA nick end labeling method.


RESULTS
Cyproterone acetate depressed testicular weight, suppressed tumor growth, and decreased both cytosolic-androgen receptor and nuclear-androgen receptor levels dose-dependently. Numbers of proliferating cell nuclear antigen-positive cells were decreased transiently with the low dose but continuously with the high dose of cyproterone acetate. Transforming growth factor-alpha expression was not influenced by cyproterone acetate, but the high dose of cyproterone acetate induced higher expression of transforming growth factor-beta 1, associated with increased numbers of apoptotic tumor cells, peaking on day 3.


CONCLUSIONS
The inhibition of growth of androgen receptor-positive hepatocellular carcinoma with cyproterone acetate in male nude mice could be due to G1-phase cell cycle arrest, and to some extent apoptosis induced by increased synthesis of transforming growth factor-beta 1 in tumor, caused by the direct action of cyproterone acetate through androgen receptors, as well as decreased testosterone levels in blood due to cyproterone acetate-induced testicular atrophy.
Nagasue
N
N
Second Department of Surgery, Shimane Medical University, Izumo, Japan.
Yu
L
L
Yamaguchi
M
M
Kohno
H
H
Tachibana
M
M
Kubota
H
H
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D017373:Cyproterone Acetate / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009929:Organ Size; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D004273:DNA, Neoplasm; D018809:Proliferating Cell Nuclear Antigen; D011944:Receptors, Androgen; D016212:Transforming Growth Factor beta; D017373:Cyproterone Acetate