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₁-Adrenergic Receptor Antagonists: Novel Therapy for Pituitary Adenomas

Division of Endocrinology, Cedars-Sinai Research Institute-Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Anthony Heaney, Division of Endocrinology, B-127, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail: HeaneyA{at}cshs.org.

Pituitary tumors are common and cause considerable morbidity due to local invasion and altered hormone secretion. Doxazosin (dox), a selective 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 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 -adrenergic receptor-expressing pituitary tumor cells and were unaffected by cotreatment with the -adrenergic receptor blocker, phenoxybenzamine. dox treatment led to reduced phosphorylated inhibitory B (IB)- expression, and nuclear factor-B transcription and decreased basal and TNF-induced proopiomelanocortin transcriptional activation. These results demonstrate that the selective ₁-adrenergic receptor antagonist dox inhibits pituitary tumor cell growth in vitro and in vivo by mechanisms that are in part independent of its -adrenergic receptor-blocking actions and involve down-regulation of nuclear factor-B signaling. dox is proposed as a possible novel medical therapy for pituitary tumors.

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