Instituto de Biología y Medicina Experimental - CONICET, Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, Argentina.
Br J Pharmacol. 2012 May;166(2):721-36. doi: 10.1111/j.1476-5381.2011.01791.x.
β-Adrenoceptors are expressed in human and experimental animal breast cancer cells. However, the effect of the agonists and antagonists reported on cell proliferation and tumour growth was paradoxical, precluding their utilization as possible adjuvant therapy, mainly in the cases of refractory tumours.
β-Adrenoceptor expression was analysed by immunofluorescence and RT-PCR. Cell proliferation was assessed by [(3) H]-thymidine incorporation, tumour growth by measuring with a calliper and ERK 1/2 phosphorylation by Western blotting.
β(2) -Adrenoceptor expression was confirmed in the mouse and human cells tested. Cell proliferation was increased by adrenaline (by α(2) -adrenoceptor action) and decreased in every tested cell line by the β-adrenoceptor agonist isoprenaline and the β(2) -adrenoceptor agonist salbutamol. Isoprenaline and salbutamol reduced tumour growth in every tumour tested (mouse C4-HD and CC4-3-HI and human IBH-4, IBH-6 and MDA-MB-231 cell lines growing as xenografts in nude mice). These effects were reversed by the β-adrenoceptor antagonist propranolol. The α(2) -adrenoceptor antagonist rauwolscine and the β(2) -adrenoceptor agonist salbutamol were equally effective in diminishing tumour growth. ERK 1/2 activation analysed in IBH-4 tumours correlated with tumour growth, with the β-adrenoceptor agonists decreasing its activation. Inhibition of ERK 1/2 phosphorylation in vitro was mainly mediated by the PKA pathway.
In our experimental models, the β-adrenoceptor agonists inhibited breast cancer cell proliferation and tumour growth, probably mediated by inhibition of ERK 1/2 phosphorylation. The β-adrenoceptor agonists were as effective as the α(2) -adrenoceptor antagonist rauwolscine, providing possible novel adjuvant treatments for breast cancer.
β-肾上腺素受体存在于人类和实验动物的乳腺癌细胞中。然而，报告的激动剂和拮抗剂对细胞增殖和肿瘤生长的影响是矛盾的，这使得它们无法被用作辅助治疗，主要是在难治性肿瘤的情况下。
通过免疫荧光和 RT-PCR 分析 β-肾上腺素受体的表达。通过[(3)H]-胸苷掺入评估细胞增殖，通过卡尺测量评估肿瘤生长，通过 Western blot 分析 ERK 1/2 磷酸化。
在测试的小鼠和人细胞中证实了β(2)-肾上腺素受体的表达。肾上腺素（通过α(2)-肾上腺素受体作用）增加了细胞增殖，而在每一种测试的细胞系中，β-肾上腺素受体激动剂异丙肾上腺素和β(2)-肾上腺素受体激动剂沙丁胺醇都降低了细胞增殖。异丙肾上腺素和沙丁胺醇降低了每一种测试肿瘤（在裸鼠中作为异种移植物生长的小鼠 C4-HD 和 CC4-3-HI 以及人 IBH-4、IBH-6 和 MDA-MB-231 细胞系）的肿瘤生长。这些作用被β-肾上腺素受体拮抗剂普萘洛尔逆转。α(2)-肾上腺素受体拮抗剂劳洛昔芬和β(2)-肾上腺素受体激动剂沙丁胺醇在减少肿瘤生长方面同样有效。IBH-4 肿瘤中分析的 ERK 1/2 激活与肿瘤生长相关，β-肾上腺素受体激动剂降低了其激活。体外抑制 ERK 1/2 磷酸化主要是通过 PKA 途径介导的。
在我们的实验模型中，β-肾上腺素受体激动剂抑制乳腺癌细胞增殖和肿瘤生长，可能是通过抑制 ERK 1/2 磷酸化介导的。β-肾上腺素受体激动剂与α(2)-肾上腺素受体拮抗剂劳洛昔芬同样有效，为乳腺癌提供了可能的新辅助治疗方法。
