Chemoprevention of lung cancer with the β-blocker carvedilol - Abstract
Lung cancer is the leading cause of cancer-related death for both men and women. Chronic exposure to
carcinogens that are present in tobacco smoking or air pollution is a known factor causing lung cancer. Although
the most important strategy to manage lung cancer is prevention, no effective chemopreventive agents currently
exist. Carvedilol is an FDA-approved oral β-blocker for cardiovascular diseases with safety records for long term
use. It displays cancer-preventive properties against chemical carcinogen-induced skin hyperplasia and
ultraviolet-induced squamous carcinoma development in mice after oral or topical administration. However, as
a very potent β-blocker, carvedilol may induce unwanted side effects due to high-level β-adrenergic receptors in
the respiratory and cardiovascular system. Interestingly, the clinical form of carvedilol is racemic, consisting of
equal amount of S- and R-carvedilol: although S-carvedilol is a β-blocker, R-carvedilol enantiomer does not
exhibit β-blocker activity and did not affect blood pressure and heart rate in mice. Since our previous study
suggests that carvedilol prevents skin cancer independently of β-blockade, we hypothesized that both the racemic
carvedilol and R-carvedilol are able to prevent lung carcinogenesis induced by tobacco carcinogen. Supporting
this hypothesis, our preliminary studies demonstrate that carvedilol, S- and R-carvedilol had similar protective
activity against single dose benzo(a)pyrene-induced oxidative stress and inflammation in mice. In addition,
carvedilol, S- and R-carvedilol similarly blocked EGF-induced malignant transformation of mouse epidermal
cells and activation of the transcription factor ELK-1 which is a promoter of lung carcinogenesis. Therefore, in
this application, we propose to evaluate the chemopreventive efficacy and mechanism for both carvedilol and R-
carvedilol using in vitro and in vivo lung carcinogenesis models induced by the prototypical tobacco carcinogen
benzo(a)pyrene. Aim 1 is to examine the effects of carvedilol and R-carvedilol in benzo(a)pyrene-induced
transformation, DNA damage and oncogenic signaling in non-tumorous human bronchial epithelial cell cultures
and to determine whether the cancer preventive activity is dependent on the β-adrenergic signaling. Aim 2 is to
determine the chemopreventive efficacy of carvedilol and R-carvedilol in a mouse model of lung cancer induced
by benzo(a)pyrene. Since carvedilol and R-carvedilol are FDA approved agents, the outcome from this project
should be readily translated into a clinical lung cancer chemoprevention regimen. R-carvedilol, lacking β-
blocking activity, is expected with improved therapeutic window without disturbance on the normal
cardiovascular and respiratory physiology.
