[Inhibitory effect of doxazosin on the growth of transplanted tumor of prostate cancer cell PC-3 in nude mice].
OBJECTIVE
To investigate the effects of alpha1 adrenoceptor antagonist doxazosin on the growth of androgen-independent prostate cancer cell PC-3 transplanted in nude mice.


METHODS
PC-3 cells xenografts were transplanted (s.c.) in nude mice, and thirty xenografts were established successively. They were then randomly divided into 5 groups: A (control group), B (doxazosin 3 mg/kg), C (doxazosin 10 mg/kg), D (doxazosin 30 mg/kg), and E (doxazosin 100 mg/kg). Seven days after implantation, doxazosin was administered in sterile water by oral gavage, and the volumes of the transplanted tumors were measured during the therapy twice a week. All the mice were sacrificed after two weeks of doxazosin administration; the tumors were resected to do the following research. Immunohistochemistry of Ki67 and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) was done to study the effects of doxazosin on the proliferation and apoptosis of prostate cancer cells; moreover, we also used Western blotting to study the protein expression of Smad-4 and IkappaB alpha.


RESULTS
Nude mouse experiments showed that the in vivo doxazosin administration induced a notable decrease in the volumes of prostate cancer xenografts compared with the control group, and the tumor weights were also decreased. Interestingly enough, administration of doxazosin at higher concentrations (10, 30, 100 mg/kg) did not have further effect on tumor suppression. The percentage of PC-3 TUNEL positive cells was significantly higher than that of the control group; while the doxazosin treated groups and the control group did not have statistical difference on the percentage of Ki67 positive cells. In doxazosin treated groups Smad-4 and IkappaB alpha expressions were higher than that of the control group.


CONCLUSIONS
Doxazosin can inhibit the growth of the prostate xenografts in the nude mice by inducing apoptosis without affecting the cell proliferation. Activation of transforming growth factor beta1 (TGF-beta1) signaling pathway may be the mechanism underlying doxazosin-mediated apoptosis.
Guo
Chang-yong
CY
Department of Urology, Peking University People's Hospital, Beijing 100044, China.
Wang
Xiao-feng
XF
Xu
Ke-xin
KX
Dong
Jian-qiang
JQ
Huang
Xiao-bo
XB
Liu
Shi-jun
SJ
Xu
Tao
T
Ye
Hai-yun
HY
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D017292:Doxazosin / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction; D051901:Smad4 Protein / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; D019394:Ki-67 Antigen; C000606205:Nfkbia protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D053773:Transforming Growth Factor beta1; D000072000:NF-KappaB Inhibitor alpha; D017292:Doxazosin