权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Chemoprevention of lung cancer with the β-blocker carvedilol

用β受体阻滞剂卡维地洛对肺癌进行化学预防

基本信息

批准号：
10348163
负责人：
Ying Huang
金额：
$ 7.05万
依托单位：
WESTERN UNIVERSITY OF HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348163
关键词：
Adrenergic Agents Adrenergic Antagonists Affinity Air Pollution Benzo(a)pyrene Biological Markers Blood Pressure Cancer Etiology Carcinogens Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cell Culture Techniques Cells Cessation of life Chemoprevention Chemopreventive Agent Chronic Clinical Cohort Studies DNA Damage Development Dose Epidermal Growth Factor Exposure to FDA approved Future Goals Heart Rate Human In Vitro Inflammation Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Modeling Mus Natural Products Oncogenic Oral Oral Administration Outcome Oxidative Stress Patients Pre-Clinical Model Prevention Preventive Property Receptor Signaling Records Regimen Reporting Respiratory System Respiratory physiology Risk Role Safety Signal Transduction Squamous cell carcinoma Therapeutic Tobacco smoking behavior Tobacco-Associated Carcinogen Topical application Transcriptional Activation Translating UV induced Woman anti-cancer beta-adrenergic receptor bronchial epithelium cancer chemoprevention cancer initiation cancer type carvedilol chemical carcinogen design elk-1 protein enantiomer improved in vivo lung cancer prevention lung carcinogenesis men mouse model novel population based prevent promoter protective effect receptor expression side effect skin cancer prevention skin hyperplasia tobacco prevention translational study tumor

项目摘要

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.

摘要肺癌是男性和女性癌症相关死亡的主要原因。长期暴露于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。虽然肺癌最重要的治疗策略是预防，目前尚无有效的化学预防药物存在.卡维地洛是FDA批准的用于心血管疾病的口服β受体阻滞剂，具有长期的安全性记录使用.它对化学致癌物诱导的皮肤增生显示出防癌特性，经口或局部给药后，小鼠中紫外线诱导的鳞状细胞癌发展。但随着卡维地洛是一种非常有效的β受体阻滞剂，由于高水平的β肾上腺素能受体，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，由以下组成：等量的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显示β-阻滞剂活性，并且不影响小鼠的血压和心率。自从我们之前的研究提示卡维地洛预防皮肤癌不依赖于β-受体阻滞剂，我们假设外消旋卡维地洛和β-受体阻滞剂都可以预防皮肤癌。卡维地洛和R-卡维地洛能预防烟草致癌物诱发的肺癌。支持我们的初步研究表明，卡维地洛、S-卡维地洛和R-卡维地洛具有相似的保护作用，抗小鼠中单剂量苯并（a）芘诱导的氧化应激和炎症的活性。此外，本发明还提供了一种方法，卡维地洛、S-卡维地洛和R-卡维地洛类似地阻断EGF诱导的小鼠表皮恶性转化细胞和激活转录因子ELK-1，这是肺癌发生的启动子。因此在本申请中，我们建议评估卡维地洛和R- 卡维地洛在烟草致癌物诱发肺癌模型中的应用苯并（a）芘。目的：1.研究卡维地洛和R-卡维地洛对苯并（a）芘诱导的大鼠心肌细胞凋亡的影响，非肿瘤人支气管上皮细胞培养物中的转化、DNA损伤和致癌信号转导并确定癌症预防活性是否依赖于β-肾上腺素能信号传导。目标二是测定卡维地洛和R-卡维地洛在肺癌诱导的小鼠模型中的化学预防功效苯并（a）芘由于卡维地洛和R-卡维地洛是FDA批准的药物，本项目的结果应该很容易转化为临床肺癌化学预防方案。R-卡维地洛，缺乏β- 阻断活性，预期具有改善的治疗窗，而不干扰正常心血管和呼吸生理学。