α₂‐Adrenoceptor action on cell proliferation and mammary tumour growth in mice

Abstract

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 a 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 a 2 -adrenoceptors in a reliable model of breast cancer. Experimental approach: The expression of a 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 a 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 a 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: a 2 -Adrenoceptor agonists enhanced tumour growth and rauwolscine behaved in vivo as a reverse agonist, suggesting that it may be tested for adjuvant treatment.

Association of alpha2a and beta2 adrenoceptor expression with clinical outcome in breast cancer

“…The use of targeted therapeutic antagonists to inhibit Epinephrine and norepinephrine, which are typically released during stress, bind to different adrenergic receptors (ARs) that mediate their effect on the control of the cardiovascular and respiratory systems. The effects of AR expression and activity in breast cancer have been investigated in recent decades, and a2 AR antagonists have been shown to inhibit the growth of breast cancer cells 4 . However, the role of beta adrenergic compounds on cell proliferation remains controversial.…”

Influence of Dexmedetomidine on Toxicity of Intrathecal Ketamine on Neonatal Rat Spinal Function

“…Nevertheless, the considerable decrease in the level of Iba1 in the pups treated with dexmedetomidine either alone or along with ketamine is suggestive of the protective effect of dexmedetomidine. Studies have shown the neuro-protective properties of dexmedetomidine [31]. These data suggested that dexmedetomidine might be helpful in reducing the neurotoxicity induced by local anaesthetics.…”

525 Effect of 5-Ht7 Receptor Blockade on Liver Regeneration After Partial Hepatectomy

“…Although only α 1 -adrenoreceptors have been reported to participate in liver regeneration, the observed inhibitory effect by SB-269970 could also be attributed to α 2 -receptor blockade especially since α 2 -adrenoreceptors are expressed in hepatocytes [42,43]. Activation of α 2 -adrenergic receptors has been reported to induce cell proliferation in different cell types [44][45][46], whereas competitive inhibition of these receptors attenuates cell proliferation and/or induces apoptosis [44,45,47]. However, there are reports that connect α 2 -receptor stimulation with inhibition of cell growth [48].…”