title: Alpha2-adrenoceptor action on cell proliferation and mammary tumour growth in mice.
abstract: OBJECTIVE
  Breast cancer, the most common cancer in women in most countries, is a highly stressful disease. Catecholamines released during stress bind to adrenoceptors and we have recently described alpha(2)-adrenoceptors in human breast cell lines, linked to enhanced cell proliferation. The purpose was to assess the in vivo effects of compounds acting on alpha(2)-adrenoceptors in a reliable model of breast cancer.
  
  
  METHODS
  The expression of alpha(2)-adrenoceptors was confirmed by immunocytochemistry, immunofluorescence and reverse transcription-PCR in the mouse mammary tumour cell line MC4-L5. Proliferation was assessed by [(3)H]thymidine incorporation and tumours were measured daily. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick-end labelling.
  
  
  RESULTS
  Incubation for 2 days with alpha(2)-adrenoceptor agonists (clonidine and dexmedetomidine) significantly enhanced proliferation of the mouse mammary tumour cell line MC4-L5. These agonists also significantly stimulated tumour growth of the progestin-dependent tumour C4-HD even in the presence of medroxyprogesterone acetate (MPA). In every tumour tested (C4-HD, CC4-2-HD and CC4-3-HI), regardless of MPA sensitivity, clonidine significantly enhanced tumour growth in the absence of MPA. The alpha(2)-adrenoceptor antagonists, yohimbine and rauwolscine, completely reversed the effects of clonidine. However, the group receiving yohimbine alone showed a nonsignificant but constant increase in tumour growth, whereas rauwolscine alone diminished tumour growth significantly, behaving as a reverse agonist. In CC4-3-HI tumours, rauwolscine treatment enhanced apoptosis and diminished the mitotic index, whereas clonidine had the inverse effect.
  
  
  CONCLUSIONS
  Alpha(2)-adrenoceptor agonists enhanced tumour growth and rauwolscine behaved in vivo as a reverse agonist, suggesting that it may be tested for adjuvant treatment.
authors.affiliation: Hormones and Cancer Laboratory, Instituto de Biología y Medicina Experimental CONICET, Buenos Aires, Argentina.
authors.forename: A
authors.initials: A
authors.lastname: Bruzzone
authors.forename: C Pérez
authors.initials: CP
authors.lastname: Piñero
authors.forename: L F
authors.initials: LF
authors.lastname: Castillo
authors.forename: M G
authors.initials: MG
authors.lastname: Sarappa
authors.forename: P
authors.initials: P
authors.lastname: Rojas
authors.forename: C
authors.initials: C
authors.lastname: Lanari
authors.forename: I A
authors.initials: IA
authors.lastname: Lüthy
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology; D020927:Dexmedetomidine / Q000494:pharmacology; D054314:Drug Inverse Agonism; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D020927:Dexmedetomidine; D017258:Medroxyprogesterone Acetate; D003000:Clonidine