Alpha1-adrenergic receptor antagonists: novel therapy for pituitary adenomas.
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.
Fernando
Manory A
MA
Division of Endocrinology, B-127, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
Heaney
Anthony P
AP
D049913:ACTH-Secreting Pituitary Adenoma / Q000188:drug therapy*; D000236:Adenoma / Q000188:drug therapy*; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017292:Doxazosin / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D011333:Pro-Opiomelanocortin / Q000235:genetics; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D018340:Receptors, Adrenergic, alpha-1; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D017292:Doxazosin