α1-Adrenergic Receptor Antagonists: Novel Therapy for Pituitary Adenomas

Abstract

Pituitary tumors are common and cause considerable morbidity due to local invasion and altered hormone secretion. Doxazosin (dox), a selective alpha(1)-adrenergic receptor antagonist, used to treat hypertension, also inhibits prostate cancer cell proliferation. We examined the effects of dox on murine and human pituitary tumor cell proliferation in vitro and in vivo. dox treatment inhibited proliferation of murine pituitary tumor cells, induced G(0)-G(1) cell cycle arrest, and reduced phosphorylated retinoblastoma levels. In addition, increased annexin-fluorescein isothiocyanate immunoreactivity and cleaved caspase-3 levels, in keeping with dox-mediated apoptosis, were observed in the human and murine pituitary tumor cells, and dox administration to mice, harboring corticotroph tumors, decreased tumor growth and reduced plasma ACTH levels. dox-mediated antiproliferative and proapoptotic actions were not confined to alpha-adrenergic receptor-expressing pituitary tumor cells and were unaffected by cotreatment with the alpha-adrenergic receptor blocker, phenoxybenzamine. dox treatment led to reduced phosphorylated inhibitory kappaB (IkappaB)-alpha expression, and nuclear factor-kappaB transcription and decreased basal and TNFalpha-induced proopiomelanocortin transcriptional activation. These results demonstrate that the selective alpha(1)-adrenergic receptor antagonist dox inhibits pituitary tumor cell growth in vitro and in vivo by mechanisms that are in part independent of its alpha-adrenergic receptor-blocking actions and involve down-regulation of nuclear factor-kappaB signaling. dox is proposed as a possible novel medical therapy for pituitary tumors.

Involvement of Protein Kinase D in Phosphorylation and Increase of DNA Binding of Activator Protein 2α to Downregulate ATP-Binding Cassette Transporter A1

“…31 Several other reports showed that doxazosin downregulated NF-B signaling and induced apoptosis in some types of cells. [35][36][37] These findings are not inconsistent with our results of inhibition of PKD and AP2␣ phosphorylation by doxazosin.…”

Treatment of Cushing's disease: a mechanistic update

“…Alpha 1 adrenergic receptor antagonists have been suggested as a novel therapy for pituitary adenomas (Fernando & Heaney 2005). In murine pituitary tumor cells, doxazosin (Cardura, Cardura XL) reduced phosphorylated retinoblastoma protein levels and induced G0-G1 cell cycle arrest with decreased tumor growth and reduced plasma ACTH levels (Fernando & Heaney 2005).…”

“…In murine pituitary tumor cells, doxazosin (Cardura, Cardura XL) reduced phosphorylated retinoblastoma protein levels and induced G0-G1 cell cycle arrest with decreased tumor growth and reduced plasma ACTH levels (Fernando & Heaney 2005). Further research is required to support the observations.…”

Targeting Pituitary Tumors

“…Doxazosin-mediated antiproliferative effects have been described in prostate tumors, where increased prostate cancer cell apoptosis and decreased serum prostate-specific antigen levels were reported in patients with prostate cancer. Treatment of murine pituitary tumor corticotroph (AtT20) and gonadotroph (LβT 2 , and αT 3 ) tumor cells with doxazosin 10–30 µ M in vitro inhibited cell proliferation, increased apoptosis and slowed in vivo tumor development [29]. However, α 1 -adrenergic receptor expression was not detectable in several of the pituitary tumor cell lines, and cotreatment of the pituitary tumor cells with the noncompetitive α-adrenoreceptor blocker phenoxy benzamine and doxazosin together did not abrogate doxazosin-mediated apoptosis.…”