The β-Blocker Carvedilol Prevents Benzo(a)pyrene-Induced Lung Toxicity, Inflammation and Carcinogenesis

SIMPLE SUMMARY: 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. ABSTRACT: 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.