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 ?-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 ?-blocker, carvedilol may induce unwanted side effects due to high-level ?-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 ?-blocker, R-carvedilol enantiomer does not exhibit ?-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 ?-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 ?-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 ?- blocking activity, is expected with improved therapeutic window without disturbance on the normal cardiovascular and respiratory physiology.
The goal of this proposal is to reveal a previously unexplored role for the ?-blocker carvedilol in prevention of tobacco carcinogen-associated lung cancer. The effects of carvedilol and the non-?-blocking R-carvedilol enantiomer will be examined in preclinical models of lung cancer. The biomarkers that have been associated with carcinogen-induced lung cancer will be evaluated to identify the mechanisms for carvedilol's cancer-preventive activity. These studies will pave the way for future translational studies that hopefully benefit many patients.
