Doxazosin induces apoptosis in PTEN-positive androgen-independent PC cells via inhibition of Akt activation

Introduction. Doxazosin, a selective α1-adrenoreceptor antagonist widely used in the management of benign prostatic hyperplasia (BPH), has been shown to induce apoptosis in androgen-independent (AI) and PTEN (phosphatases and tensin homolog)-negative prostate cancer (PC) cells. The objective of this study was to assess the effects of doxazosin on the growth of PC cells with a functional PTEN/PI3K/Akt pathway in relation to cell androgen sensitivity and Bcl-2 expression. Material and methods. The DU145 cell line and two derivatives: 1) DKC9 [DU145 (Bcl2 +/+)] and 2) DAR19 [DU145 (AR+/+)] were used. The effect of doxazosin on i) cell proliferation and ii) Akt phosphorylation was measured using the MTT assay and Western blotting, respectively. Results. Doxazosin caused significant concentration, but not time-dependent, decrease in cell viability. The threshold of sensitivity to the compound differed between the cell lines and was the lowest in the parental cell line. In DAR 19 cells, AR-mediated signaling further increased cell resistance to doxazosin. In all cell lines, doxazosin-induced apoptosis was rescued by EGF stimulation and, in DAR19 cells, by AR activation. Doxazosin reduced basal and EGF-/DHT-induced Akt phosphorylation. Conclusions. This study demonstrates that doxazosin induces apoptosis in PTEN-positive AI PC cells, at least partially, via Akt deactivation and that over-expression of Bcl-2 or AR increases cell resistance to the drug. These results imply that translational potential of doxazosin depends on phenotypic characteristics of PC cells and provide evidence for limitations to its application in hormone refractory tumors.