Induction of apoptosis in the prostate by α1-adrenoceptor antagonists: A novel effect of “Old” drugs

Abstract

Advances in our understanding of the integrated functions governing prostate cell proliferation and cell death imply that effective therapies for prostate neoplasia should not only be molecularly targeted, but should be customized to take into account the delicate balance of opposing growth influences. Evidence from studies on the dynamics of prostate growth in benign prostatic hyperplasia (BPH) and prostate cancer established that disruption of the molecular mechanisms that regulate apoptosis and cell proliferation among the stroma and epithelial cell populations may underlie the neoplastic development that characterizes the aging gland. Our own efforts have been focused on investigating whether a1-adrenoceptor antagonists clinically used for the relief of the obstructive symptoms associated with BPH affect prostate pathophysiology via mechanisms other than smooth muscle contraction. Such efforts led to the identification of a novel effect of two alpha1-adrenoceptor antagonists, doxazosin and terazosin. More recent in vitro experiments examined the potential anti-tumor action of three clinically used alpha1-adrenoceptor antagonists--doxazosin, terazosin and tamsulosin--against prostate cancer cell growth. These findings demonstrate the ability of doxazosin and terazosin, but not tamsulosin, to suppress prostate growth by inducing apoptosis among the epithelial cells in the benign and malignant prostate. Thus, evidence indicates that rather than just causing pure relaxation of the smooth muscle, certain alpha1-blockers can also affect the dynamics of prostate growth by changing the balance between prostate cell proliferation and apoptosis at the expense of the proliferative process.

Caveolae Contribute to the Apoptosis Resistance Induced by the α1A-Adrenoceptor in Androgen-Independent Prostate Cancer Cells

“…However, several studies have provided evidence on additional effects of α 1 -AR antagonists such as doxazosin on long-term BPH treatment. These agents have been demonstrated to inhibit prostate growth by inducing apoptosis in stromal and epithelial cells and are emerging as potential therapeutic regimens for the prevention and treatment of androgen-independent PCa [9], [10], [11]. In addition, previous studies from co-workers on human prostate cancer epithelial (hPCE) cells and the androgen-dependent prostate cancer cell line LNCaP showed that phenylephrine (PHE), an α 1A -AR agonist, stimulates their proliferation [12], [13].…”

Doxazosin reduces cell proliferation and increases collagen fibers in rat prostatic lobes

“…Recently, Dox has also been demonstrated to inhibit prostate growth by inducing apoptosis in stromal and epithelial cells, showing additional effects on long-term BPH treatment and emerging as a potential drug for the prevention and treatment of androgen-independent PCa (Yang et al 1997;Kyprianou et al 1998;Kyprianou and Jacobs 2000;Anglin et al 2002;Kyprianou 2003;Chiang et al 2005).…”

Coupling of α₁-Adrenoceptors to ERK1/2 in the Human Prostate

“…Treatment with ␣ 1 -adrenoceptor blockers in patients with lower urinary tract symptoms is believed to relieve urine flow at least partially by a decrease in prostate smooth muscle tone [1,2,19] . However, it has been proposed that ␣ 1 -adrenoceptor blockers may act on BPH by suppression of prostate growth [20][21][22] . In BPH, the treatment with ␣ 1 -adrenoceptor blockers may result in stromal regression and reduced growth [23][24][25][26][27] .…”