Chemoprevention of lung cancer with the β-blocker carvedilol

摘要 肺癌是男性和女性癌症相关死亡的主要原因。长期接触 吸烟或空气污染中存在的致癌物质是导致肺癌的已知因素。虽然 治疗肺癌最重要的策略是预防，目前还没有有效的化学预防药物 是存在的。卡维地洛是fda批准的治疗心血管疾病的口服β阻滞剂，有长期安全记录 使用。它对化学致癌物引起的皮肤增生具有防癌作用， 口服或局部给药后紫外线诱导小鼠鳞状细胞癌的发生。然而，由于 作为一种非常有效的β阻滞剂，卡维地洛可能会由于高水平的β肾上腺素能受体而引起有害的副作用 呼吸系统和心血管系统。有趣的是，卡维地洛的临床形式是外消旋的，包括 等量S和R-卡维地洛：虽然S-卡维地洛是β阻滞剂，但R-卡维地洛对映体不是 表现出β阻滞剂活性，对小鼠的血压和心率没有影响。从我们之前的研究开始 提示卡维地洛预防皮肤癌独立于β-阻断，我们假设外消旋体 卡维地洛和R-卡维地洛可预防烟草致癌物诱发的肺癌。支座 这一假设，我们的初步研究表明，卡维地洛、S和R-卡维地洛具有类似的保护作用 对单剂量苯并(A)芘诱导的小鼠氧化应激和炎症的抑制作用。此外, 卡维地洛、S和R-卡维地洛类似地阻断表皮生长因子诱导的小鼠表皮恶性转化 细胞和转录因子ELK-1的激活，ELK-1是肺癌发生的促进剂。因此，在 在此应用中，我们建议评价卡维地洛和R-受体阻滞剂的化学预防效果和机制。 卡维地洛体外和体内烟草致癌物诱发肺癌模型的建立 苯并(A)芘。目的1是研究卡维地洛和R-卡维地洛对苯并(A)芘诱导的作用 非肿瘤性人支气管上皮细胞的转化、DNA损伤及致癌信号转导 并确定癌症预防活性是否依赖于β-肾上腺素能信号。目标2是 卡维地洛和R-卡维地洛对小鼠肺癌模型的化学预防作用 通过苯并(A)芘。由于卡维地洛和R-卡维地洛是FDA批准的药物，该项目的结果 应该容易地转化为临床肺癌的化学预防方案。R-卡维地洛，缺乏β- 阻断活动，有望在不干扰正常的情况下改善治疗窗 心血管和呼吸生理学。

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.