S- and R-Carvedilol Prevent Benzo(a)pyrene-Induced Lung Carcinogenesis.

Abstract

Lung cancer is the most common and deadly type of cancer. Our previous study showed that carvedilol, a β-blocker, can prevent lung cancer induced by benzo(a)pyrene [B(a)P]. Carvedilol is a 1:1 racemic mixture of S- and R-carvedilol, with S-carvedilol acting as a β-adrenergic blocker, while R-carvedilol lacks β-blocking activity. Despite this, a previous study showed that R-carvedilol effectively prevents UV-induced skin cancer. This study aimed to determine whether carvedilol's lung cancer prevention relies on its β-blocking activity. We compared the effectiveness of S- and R-carvedilol in preventing lung cancer induced by B(a)P and its metabolite, benzo(a)pyrene diol epoxide (BPDE), both in vivo and in vitro. Our results showed that S- and R-carvedilol equally prevent malignant transformation of the human bronchial epithelial cell line (BEAS-2B) induced by BPDE. Furthermore, both S- and R-carvedilol significantly inhibit the B(a)P-induced activation of the aryl hydrocarbon receptor (AhR)/xenobiotic responsive element (XRE) and mRNA expression of CYP1A1 in BEAS-2B cells. In mice, daily administering S- or R-carvedilol for 7 days before exposing them to B(a)P resulted in a significant decrease in the levels of lactate dehydrogenase and malondialdehyde and prevented inflammatory cell infiltration and histopathologic abnormalities in mouse lungs. Exposure to B(a)P caused the development of lung tumors, but treating the mice with S- or R-carvedilol for 23 weeks significantly reduced the number and size of these tumors. The results were confirmed by H&E-stained images of the mouse lungs. These findings support the hypothesis that carvedilol prevents B(a)P-induced lung inflammation and carcinogenesis independently of β-blockade.