The β-Blocker Carvedilol Prevents Benzo(a)pyrene-Induced Lung Toxicity, Inflammation and Carcinogenesis.
The β-Blocker Carvedilol Prevents Benzo(a)pyrene-Induced Lung Toxicity, Inflammation and Carcinogenesis.
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苯并芘是一种普遍存在的环境污染物，通过芳烃受体（AhR）介导的代谢激活转化为活性代谢物后可诱发肺癌。先前的报告表明，卡维地洛是具有皮肤癌预防活性的最有效的β受体阻滞剂之一。目前的研究评估了卡维地洛对苯并(a)芘引起的肺毒性、炎症和致癌作用的作用和机制。卡维地洛可阻断苯并(a)芘诱导的人支气管上皮细胞恶性转化，并抑制苯并(a)芘诱导的ELK-1、NF-κB和AhR致癌信号的激活。这一结果表明这些信号通路的串扰在介导肺部炎症和癌变中发挥着重要作用。卡维地洛的活性在急性肺毒性和炎症以及苯并（a）芘诱导的慢性肺癌发展的小鼠模型中得到进一步证实。作为 FDA 批准的仿制药，卡维地洛可能被重新用作肺癌预防剂。 本研究评估了β受体阻滞剂卡维地洛对苯并(a)芘(B(a)P)及其活性代谢物苯并(a)芘二醇环氧化物(BPDE)引起的肺毒性、炎症和致癌作用的影响，并探讨了其潜在机制。卡维地洛阻断 BPDE 诱导的人支气管上皮细胞 BEAS-2B 的恶性转化。在 BEAS-2B 细胞中，B(a)P 强烈激活 ELK-1，这是一种调节血清反应元件 (SRE) 信号传导的转录因子，卡维地洛可减弱这种作用。卡维地洛还抑制 B(a)P 诱导的 AhR/异生素反应元件 (XRE) 和 CYP1A1 mRNA 表达，并减弱 B(a)P 诱导的 NF-κB 激活。在B(a)P诱导的CD-1/IGS小鼠急性肺毒性模型中，B(a)P暴露前用卡维地洛预处理7天，可有效抑制B(a)P诱导的血浆乳酸脱氢酶和丙二醛水平、肺部炎症细胞浸润和组织病理学异常，并上调肺部GADD45α、caspase-3和COX-2的表达。在 B(a)P 诱导的 A/J 小鼠肺癌模型中，卡维地洛治疗 20 周不影响体重，但显着减弱肿瘤的多样性和体积。这些数据揭示了卡维地洛通过抑制致癌转录因子 ELK-1、AhR 和 NF-κB 的串扰来预防 B(a)P 诱导的肺部炎症和致癌作用，这一作用此前尚未被探索过。
Benzo(a)pyrene is a ubiquitously present environmental contaminant that induces lung cancer after being converted into active metabolites via aryl hydrocarbon receptor (AhR)-mediated metabolic activation. Previous reports showed that carvedilol is one of the most effective β-blockers with skin cancer preventive activity. The current study evaluated the effect and mechanism of carvedilol on benzo(a)pyrene-induced lung toxicity, inflammation and carcinogenesis. Carvedilol blocked the benzo(a)pyrene-induced malignant transformation of human bronchial epithelial cells and inhibited the benzo(a)pyrene-induced activation of the oncogenic signaling of ELK-1, NF-κB and AhR. This result suggests that the cross-talk of these signaling pathways plays an important role in mediating both inflammation and carcinogenesis in the lung. Carvedilol’s activity was further confirmed on mouse models of acute lung toxicity and inflammation, as well as chronic lung cancer development induced by benzo(a)pyrene. As an FDA-approved generic drug, carvedilol may be repurposed as a lung cancer preventive agent. The current study evaluated the effects of the β-blocker carvedilol on benzo(a)pyrene (B(a)P) and its active metabolite benzo(a)pyrene diol epoxide (BPDE)-induced lung toxicity, inflammation and carcinogenesis and explored the potential mechanisms. Carvedilol blocked the BPDE-induced malignant transformation of human bronchial epithelial cells BEAS-2B. In BEAS-2B cells, B(a)P strongly activated ELK-1, a transcription factor regulating serum response element (SRE) signaling, which was attenuated by carvedilol. Carvedilol also inhibited the B(a)P-induced AhR/xenobiotic responsive element (XRE) and mRNA expression of CYP1A1 and attenuated B(a)P-induced NF-κB activation. In a B(a)P-induced acute lung toxicity model in CD-1/IGS mice, pretreatment with carvedilol for 7 days before B(a)P exposure effectively inhibited the B(a)P-induced plasma levels of lactate dehydrogenase and malondialdehyde, inflammatory cell infiltration and histopathologic abnormalities in the lung, and upregulated the expression of GADD45α, caspase-3 and COX-2 in the lung. In a B(a)P-induced lung carcinogenesis model in A/J mice, carvedilol treatment for 20 weeks did not affect body weight but significantly attenuated tumor multiplicity and volume. These data reveal a previously unexplored role of carvedilol in preventing B(a)P-induced lung inflammation and carcinogenesis by inhibiting the cross-talk of the oncogenic transcription factors ELK-1, AhR and NF-κB.
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影响因子：
4.7
作者：
Chen, Wenshu;Xu, Xiuling;Lin, Yong
通讯作者：
Lin, Yong
影响因子：
2.3
作者：
Kim YS;Chung YH;Seo DS;Choi HS;Lim CH
通讯作者：
Lim CH
影响因子：
2.8
作者：
Ali, R.;Shahid, A.;Sultana, S.
通讯作者：
Sultana, S.
DOI：
10.1007/s00109-021-02163-2
发表时间：
2022-03
期刊：
Journal of molecular medicine (Berlin, Germany)
影响因子：
--
作者：
Coelho NR;Pimpão AB;Correia MJ;Rodrigues TC;Monteiro EC;Morello J;Pereira SA
通讯作者：
Pereira SA
影响因子：
4.6
作者：
Cleveland, Kristan H.;Yeung, Steven;Huang, Ying
通讯作者：
Huang, Ying