Prazosin Displays Anticancer Activity against Human Prostate Cancers: Targeting DNA, Cell Cycle

Abstract

Quinazoline-based alpha1-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 alpha1-blockers, including doxazosin, terazosin, tamsulosin, and phentolamine. Prazosin induced G2 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 Cdc25c phosphorylation at Ser216, nuclear export of Cdc25c, and cyclin-dependent kinase (Cdk) 1 phosphorylation at Tyr15. 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.

<i>Toxoplasma gondii</i> But Not <i>Leishmania major</i> or <i>Trichomonas vaginalis</i> Decreases Cell Proliferation and Increases Cell Death on Fibrosarcoma Cancer Cells in Culture Medium

“…These findings are in agreement with the hygiene theory [9][10][11]. Moreover effects of some other substances such as diphosphate [12], Parazosin [13] and dopamin [14] on malignant cells proliferation have been demonstrated. In this work in order to explore anticancer activity of parasites further, in cell culture the effects of Toxoplasma gondii and two other protozoan parasites; Trichomonas vaginalis and Leishmania major; on proliferation, apoptosis and death of mouse fibrosarcoma cells have been investigated.…”

Naftopidil, a Selective α1-Adrenoceptor Antagonist, Suppresses Human Prostate Tumor Growth by Altering Interactions between Tumor Cells and Stroma

“…Previous studies have documented the induction of apoptosis in PCa cells by subtype nonselective a 1 -AR antagonists (doxazosin, terazosin, and prazosin; refs. 5,6). In addition, the G 1 cell-cycle arrest was induced in PCa cells by subtypeselective a 1 -AR antagonist naftopidil, which is only marketed in Japan (7).…”

Prazosin induces p53-mediated autophagic cell death in H9C2 cells

“…Whereas several mechanisms and signaling pathways have been identified to explain doxazosin-induced anoikis and apoptosis in various types of cells (Eiras et al 2006;Walden et al 2004), few studies elucidate the cytotoxic effects of prazosin. However, prazosin has been shown to induce cell death through pathways distinct from those via which doxazosin exerts its effects and is a more potent antineoplastic agent than doxazosin (Lin et al 2007). We suggest that multiple mechanisms requiring further investigation are involved in prazosin-induced cell death.…”