Abstract
Introduction: Locally advanced non-small cell lung cancer (NSCLC) is highly resistant to chemoradiotherapy, and many cancer patients experience chronic stress. Studies that suggest stimulation of β-adrenergic receptors (β-AR) promotes tumor invasion and therapy resistance. We investigated whether β-AR inhibition with beta-blockers acts as a chemotherapy and radiation sensitizer in vitro and in patients treated with chemoradiation for locally advanced NSCLC. Methods: We investigated the effects of the non-selective beta-blocker propranolol on two human lung adenocarcinoma cell lines (PC9, A549) treated with radiation or cisplatin. We retrospectively evaluated 77 patients with Stage IIIA NSCLC who received induction chemoradiation followed by surgery. Pathological and imaging response, metastatic rate, and survival were analyzed using SPSS v22.0 and PrismGraphpad6. Results: Propranolol combined with radiation or cisplatin decreased clonogenic survival of PC9 and A549 cells in vitro (p < 0.05). Furthermore, propranolol decreased expression of phospho-protein kinase A (p-PKA), a β-adrenergic pathway downstream activation target, in both cell lines compared to irradiation or cisplatin alone (p < 0.05). In patients treated for Stage IIIA NSCLC, 16 took beta-blockers, and 61 did not. Beta-blockade is associated with a trend to improved overall survival (OS) at 1 year (81.3% vs 57.4%, p = 0.08) and distant metastasis-free survival (DMFS) (2.6 years vs. 1.3 years, p = 0.16). Although beta-blocker use was associated with decreased distant metastases (risk ratio (RR) 0.19; p = 0.03), it did not affect primary tumor pathological response (p = 0.40) or imaging response (p = 0.36). Conclusions: β-AR blockade enhanced radiation and cisplatin sensitivity of human lung cancer cells in vitro. Use of beta-blockers is associated with decreased distant metastases and potentially improved OS and DMFS. Additional studies are warranted to evaluate the role of beta-blockers as a chemoradiation sensitizer in locally advanced NSCLC.
Highlights
Advanced non-small cell lung cancer (NSCLC) is highly resistant to chemoradiotherapy, and many cancer patients experience chronic stress
Nicotine stimulates the secretion of neurotropic factors epinephrine and norepinephrine, which in turn bind β-adrenergic receptors (β-AR), leading to a host of downstream oncogenic signaling cascades including the epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and mitogen-activated protein kinase (MAPK known as RAS/Raf/MEK/ERK) pathways [5,6,7,8,9]
We investigated whether β-AR inhibition with beta-adrenergic receptor antagonists, or beta-blockers, results in increased cisplatin and radiation sensitivities in vitro and differential treatment outcomes in patients treated with chemoradiation followed by surgery for locally advanced stage IIIA NSCLC
Summary
Concurrent chemoradiation therapy is a standard treatment for non-small cell lung cancer (NSCLC) patients with locally advanced disease. The exact mechanisms of how beta-blockers confer their antitumor activity in lung cancers have yet to be understood The use of this class of medication as a sensitizer in treatment of locally advanced NSCLC with concurrent chemoradiation remains to be further explored. We investigated whether β-AR inhibition with beta-adrenergic receptor antagonists, or beta-blockers, results in increased cisplatin and radiation sensitivities in vitro and differential treatment outcomes in patients treated with chemoradiation followed by surgery for locally advanced stage IIIA NSCLC. We hypothesized that beta-blockers increase cisplatin and radiation sensitivity of human lung cancer cells, and beta-blocker use confers survival benefit in patients treated for locally advanced NSCLC
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