β2-肾上腺素能激动剂沙丁胺醇抑制人乳腺癌 MDA-MB-231 细胞系的迁移、侵袭和转移。

The β 2-Adrenergic Agonist Salbutamol Inhibits Migration, Invasion and Metastasis of the Human Breast Cancer MDA-MB- 231 Cell Line.

机构信息

Instituto de Biología y Medicina Experimental, IBYME-CONICET, Buenos Aires. Argentina.

Institute for Immunology, ZBAF, Witten/Herdecke University, Witten. Germany.

出版信息

Curr Cancer Drug Targets. 2017;17(8):756-766. doi: 10.2174/1568009617666170330151415.

DOI:10.2174/1568009617666170330151415

PMID:28359245

Abstract

BACKGROUND

Breast cancer is the most diagnosed and the major cause of cancer death in women worldwide. Metastasis is the main cause of these deaths. The metastatic cascade involves multiple steps and it has been described that adrenergic receptors can modulate this process at multiple levels. However, β -adrenergic action in breast cancer is controversial. We have previously shown that β-adrenergic agonists inhibit cell proliferation and tumor growth of numerous breast cancer models.

OBJECTIVE

The purpose of the present investigation was to evaluate adrenergic effect in parameters related to tumor progression (migration, invasion and metastases) in two human breast cancer cell lines.

METHODS

Migration was assessed in IBH-6 and MDA-MB-231 cells by time-lapse videomicroscopy and modified Boyden chambers. Invasion was evaluated by Transwells coated with Matrigel and expression of pro-metastatic genes was determined by RT-qPCR. Experimental metastases studies were performed by injection of the cells in the tail vein of NSG immuno-deficient mice.

RESULTS

In both cell lines, salbutamol (β2-agonist) and propranolol (β-blocker) significantly diminished cell migration while epinephrine exerted opposite effects. Moreover, salbutamol inhibited invasion of both breast cancer cell lines and enhanced adhesion to extracellular matrix. Salbutamol treatment was also able to decrease the expression of pro-metastatic genes in MDA-MB-231 cells. Finally, this compound decreased the number and size of MDA-MB-231 lung experimental metastases in NSG immuno- deficient mice. No effect on the establishment of IBH-6 metastases was observed.

CONCLUSION

Our results suggest that salbutamol could be an effective adjuvant drug for the treatment of metastatic breast cancer.

摘要

背景

乳腺癌是全球女性最常见的诊断和癌症死亡原因。转移是导致这些死亡的主要原因。转移级联反应涉及多个步骤，已经描述了肾上腺素能受体可以在多个水平上调节这个过程。然而，β-肾上腺素能在乳腺癌中的作用存在争议。我们之前已经表明，β-肾上腺素能激动剂可以抑制多种乳腺癌模型的细胞增殖和肿瘤生长。

目的

本研究的目的是评估肾上腺素能在与肿瘤进展（迁移、侵袭和转移）相关的参数中对两种人乳腺癌细胞系的影响。

方法

通过时差视频显微镜和改良 Boyden 室评估 IBH-6 和 MDA-MB-231 细胞的迁移。通过 Transwell 评估侵袭，并用 Matrigel 包被，并通过 RT-qPCR 确定促转移基因的表达。通过将细胞注射到 NSG 免疫缺陷小鼠的尾静脉中来进行实验性转移研究。

结果

在两种细胞系中，沙丁胺醇（β2-激动剂）和普萘洛尔（β-阻滞剂）显著减少细胞迁移，而肾上腺素则产生相反的作用。此外，沙丁胺醇抑制了两种乳腺癌细胞系的侵袭，并增强了细胞对细胞外基质的黏附。沙丁胺醇治疗还能够降低 MDA-MB-231 细胞中促转移基因的表达。最后，该化合物减少了 MDA-MB-231 肺实验转移的数量和大小在 NSG 免疫缺陷小鼠中。在 IBH-6 转移的建立中没有观察到效果。