Chaudhary Kunal R, Yan Sherry X, Heilbroner Samuel P, Sonett Joshua R, Stoopler Mark B, Shu Catherine, Halmos Balazs, Wang Tony J C, Hei Tom K, Cheng Simon K
Department of Radiation Oncology, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA.
Division of Cardiac, Vascular and Thoracic Surgery, Department of Surgery, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA.
J Clin Med. 2019 Apr 26;8(5):575. doi: 10.3390/jcm8050575.
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.
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.
Propranolol combined with radiation or cisplatin decreased clonogenic survival of PC9 and A549 cells in vitro ( < 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 ( < 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%, = 0.08) and distant metastasis-free survival (DMFS) (2.6 years vs. 1.3 years, = 0.16). Although beta-blocker use was associated with decreased distant metastases (risk ratio (RR) 0.19; = 0.03), it did not affect primary tumor pathological response ( = 0.40) or imaging response ( = 0.36).
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.
局部晚期非小细胞肺癌（NSCLC）对放化疗具有高度抗性，许多癌症患者会经历慢性应激。有研究表明，刺激β-肾上腺素能受体（β-AR）会促进肿瘤侵袭和治疗抗性。我们调查了使用β受体阻滞剂抑制β-AR是否在体外以及在接受放化疗的局部晚期NSCLC患者中起到化疗和放疗增敏剂的作用。
我们研究了非选择性β受体阻滞剂普萘洛尔对两种接受放疗或顺铂治疗的人肺腺癌细胞系（PC9、A549）的影响。我们回顾性评估了77例IIIA期NSCLC患者，这些患者接受了诱导放化疗然后进行手术。使用SPSS v22.0和PrismGraphpad6分析病理和影像反应、转移率及生存率。
普萘洛尔联合放疗或顺铂降低了体外PC9和A549细胞的克隆形成存活率（<0.05）。此外，与单独放疗或顺铂相比，普萘洛尔降低了两种细胞系中磷酸化蛋白激酶A（p-PKA）的表达，p-PKA是β-肾上腺素能途径下游的激活靶点（<0.05）。在接受IIIA期NSCLC治疗的患者中，16例服用了β受体阻滞剂，61例未服用。β受体阻滞剂的使用与1年总生存期（OS）改善趋势相关（81.3%对57.4%，P = 0.08）以及无远处转移生存期（DMFS）相关（2.6年对1.3年，P = 0.16）。虽然使用β受体阻滞剂与远处转移减少相关（风险比（RR）0.19；P = 0.03），但它不影响原发肿瘤的病理反应（P = 0.40）或影像反应（P = 0.36）。
β-AR阻断在体外增强了人肺癌细胞对放疗和顺铂的敏感性。使用β受体阻滞剂与远处转移减少以及潜在的OS和DMFS改善相关。有必要进行更多研究以评估β受体阻滞剂作为局部晚期NSCLC放化疗增敏剂的作用。
