Prazosin Displays Anticancer Activity against Human Prostate Cancers: Targeting DNA and Cell Cycle.
Resource
NEOPLASIA v.9 n.10 pp.830-839
Journal
NEOPLASIA
Journal Volume
v.9
Journal Issue
n.10
Pages
830-839
Date Issued
2007
Date
2007
Author(s)
LIN, SSU-CHIA
CHUEH, SHIH-CHIEH
HSIAO, CHE-JEN
LI, TSAI-KUN
CHEN, TZU-HSUAN
LIAO, CHO-HWA
LYU, PING-CHIANG
GUH, JIH-HWA
Abstract
Quinazoline-based alpha(1)-adrenoceptor antagonists, in particular doxazosin and terazosin, are suggested to display antineoplastic activity against prostate cancers. However, there are few studies elucidating the effect of prazosin. In this study, prazosin displayed antiproliferative activity superior to that of other alpha(1)-blockers, including doxazosin, terazosin, tamsulosin, and phentolamine. Prazosin induced G(2) checkpoint arrest and subsequent apoptosis in prostate cancer PC-3, DU-145, and LNCaP cells. In p53-null PC-3 cells, prazosin induced an increase in DNA strand breaks and ATM/ ATR checkpoint pathways, leading to the activation of downstream signaling cascades, including Cdc25 c phosphorylation at Ser 216, nuclear export of Cdc25c, and cyclin-dependent kinase (Cdk) 1 phosphorylation at Tyr(15). The data, together with sustained elevated cyclin A levels( other than cyclin B1 levels), suggested that Cdk1 activity was inactivated by prazosin. Moreover, prazosin triggered mitochondria-mediated and caspase-executed apoptotic pathways in PC-3 cells. The oral administration of prazosin significantly reduced tumor mass in PC-3-derived cancer xenografts in nude mice. In summary, we suggest that prazosin is a potential antitumor agent that induces cell apoptosis through the induction of DNA damage stress, leading to Cdk1 inactivation and G2 checkpoint arrest. Subsequently, mitochondria-mediated caspase cascades are triggered to induce apoptosis in PC-3 cells.
Subjects
prazosin
DNA damage
cell cycle
Cdc25c
mitochondria-involved apoptosis
SDGs