Alpha2-adrenoceptor action on cell proliferation and mammary tumour growth in mice

Br J Pharmacol. 2008 Oct;155(4):494-504. doi: 10.1038/bjp.2008.278. Epub 2008 Jul 7.


Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists*
  • Adrenergic alpha-2 Receptor Antagonists
  • Adrenergic alpha-Agonists / pharmacology*
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Clonidine / pharmacology
  • Dexmedetomidine / pharmacology
  • Drug Inverse Agonism
  • Female
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / physiopathology
  • Medroxyprogesterone Acetate / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Yohimbine / pharmacology


  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-2 Receptor Antagonists
  • Adrenergic alpha-Agonists
  • Adrenergic alpha-Antagonists
  • Receptors, Adrenergic, alpha-2
  • Yohimbine
  • Dexmedetomidine
  • Medroxyprogesterone Acetate
  • Clonidine