α1-Adrenergic Receptor Antagonists: Novel Therapy for Pituitary Adenomas

Abstract

Abstract Pituitary tumors are common and cause considerable morbidity due to local invasion and altered hormone secretion. Doxazosin (dox), a selective α1-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 G0-G1 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 α-adrenergic receptor-expressing pituitary tumor cells and were unaffected by cotreatment with the α-adrenergic receptor blocker, phenoxybenzamine. dox treatment led to reduced phosphorylated inhibitory κB (IκB)-α expression, and nuclear factor-κB transcription and decreased basal and TNFα-induced proopiomelanocortin transcriptional activation. These results demonstrate that the selective α1-adrenergic receptor antagonist dox inhibits pituitary tumor cell growth in vitro and in vivo by mechanisms that are in part independent of its α-adrenergic receptor-blocking actions and involve down-regulation of nuclear factor-κB signaling. dox is proposed as a possible novel medical therapy for pituitary tumors.