Oral treatment of the TRAMP mice with doxazosin suppresses prostate tumor growth and metastasis.
BACKGROUND
We used the TRAMP mouse model for testing the effect of oral doxazosin treatment on the in vivo prostate tumor growth and metastasis.


METHODS
Five groups of TRAMP mice at different ages were orally fed with 1 mg/kg of doxazosin or DMSO for 45-196 days. At the end of oral treatment, tumor weight was determined, and metastasis to multiple organs examined. The levels of MUC18, Bcl-2, Bax, caspase-3, poly (ADP-ribose) polymerase (PARP), phospho (Ser473)-AKT, and Ki-67 in the mouse prostate tumors were determined.


RESULTS
Oral treatment of the TRAMP mice with doxazosin for 45-81 days did not decrease the size of preexisting prostate tumors, but it limited the metastasis to peri-aortic lymph nodes. A prolonged treatment of TRAMP mice with doxazosin (156-196 days), if administered early, decreased the prostate tumor weight and completely suppressed metastasis. The doxazosin treatment did not further decrease the expression of an already low level of Bcl-2 in all prostate tumors, but it increased the expression of Bax, and the activation of caspase-3, and the cleavage of a downstream substrate, PARP. The treatment reduced the expression of MUC18, phospho (Ser473)-AKT, and Ki-67. The treatment in the early phase appeared to promote prostate tumor growth and increased the expression of a proliferative index, Ki-67.


CONCLUSIONS
Doxazosin, if administered early, may be useful for preventing the prostate tumor formation, and also for limiting or completely suppressing the metastasis of prostate cancer in the TRAMP model. The mechanism of doxazosin is consistent with the established hypothesis.
Chiang
Cheng-Feng
CF
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Son
Eugene Lee
EL
Wu
Guang-Jer
GJ
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000727:Androgen-Binding Protein / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D051929:CD146 Antigen; D053148:Caspase 3; D020169:Caspases / Q000235:genetics; D004195:Disease Models, Animal; D017292:Doxazosin / Q000494:pharmacology*; D005260:Female; D019394:Ki-67 Antigen / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019006:Neural Cell Adhesion Molecules / Q000235:genetics; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051028:bcl-2-Associated X Protein
D000317:Adrenergic alpha-Antagonists; D000727:Androgen-Binding Protein; D015703:Antigens, CD; C494827:Bax protein, mouse; D051929:CD146 Antigen; D019394:Ki-67 Antigen; C497903:Mcam protein, mouse; D019006:Neural Cell Adhesion Molecules; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C027519:probasin; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D017292:Doxazosin