The alpha1-adrenoceptor antagonist terazosin induces prostate cancer cell death through a p53 and Rb independent pathway.
Prostate cancer is the second leading cause of cancer-related death in men. Treatment failure in prostate cancer is usually due to the development of androgen independence and resistance to chemotherapeutic drugs at an advanced stage. Recently, it was reported that the alpha1-adrenoceptor antagonist terazosin was able to inhibit prostate cancer cell growth and indicated that it may have an implication in the treatment of prostate cancer. The aim of the present study was to investigate the mechanisms involved in terazosin-induced prostate cancer cell death using two androgen-independent cell lines, PC-3 and DU145. Our results showed that terazosin inhibited not only prostate cancer cell growth but also colony forming ability, which is the main target of chemotherapy. We also found that the sensitivity of these cells to terazosin was not affected by the presence of either functional p53 or Rb, suggesting that the terazosin-induced cell death was independent of p53 and Rb. However, the terazosin-induced cell death was associated with G1 phase cell cycle arrest and up-regulation of p27KIP1. In addition, up-regulation of Bax and down-regulation of Bcl-2 was also observed indicating that these two apoptotic regulators may play important roles in terazosin-mediated cell death pathway. Our results provide evidence for the first time that terazosin may have a therapeutic potential in the treatment of advanced prostate cancer.
Xu
Kexin
K
Department of Urology, People's Hospital, Beijing, China.
Wang
Xianghong
X
Ling
Patrick M T
PM
Tsao
S W
SW
Wong
Y C
YC
D058668:Adrenergic alpha-1 Receptor Antagonists; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D003114:Colony-Forming Units Assay; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D008297:Male; D011224:Prazosin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D015854:Up-Regulation
D058668:Adrenergic alpha-1 Receptor Antagonists; D018797:Cell Cycle Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C041226:Terazosin; D011224:Prazosin