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α 2 ‐Adrenoceptor action on cell proliferation and mammary tumour growth in mice
Author(s) -
Bruzzone A,
Piñero C Pérez,
Castillo L F,
Sarappa M G,
Rojas P,
Lanari C,
Lüthy I A
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.278
Subject(s) - rauwolscine , yohimbine , endocrinology , medicine , cell growth , biology , agonist , cell culture , receptor , antagonist , biochemistry , genetics
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 α 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 α 2 ‐adrenoceptors in a reliable model of breast cancer. Experimental approach: The expression of α 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 α 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 α 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: α 2 ‐Adrenoceptor agonists enhanced tumour growth and rauwolscine behaved in vivo as a reverse agonist, suggesting that it may be tested for adjuvant treatment. British Journal of Pharmacology (2008) 155 , 494–504; doi: 10.1038/bjp.2008.278 ; published online 7 July 2008