Preventing UV-induced immunosuppression and skin carcinogenesis with R-carvedilol

用 R-卡维地洛预防紫外线引起的免疫抑制和皮肤癌

基本信息

批准号：
10653137
负责人：
Ying Huang
金额：
$ 31.61万
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：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653137
关键词：
AR gene Adrenergic beta-Antagonists Affect Animal Experiments Applications Grants Biological Availability Blood Pressure Bradycardia Calcium Calcium Channel Carcinogens Cardiovascular Agents Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Chemoprevention Chemopreventive Agent Chronic stress Clinical Clinical Research DNA Damage Data Development Dose Drug Targeting Drug usage Ensure Exposure to FDA approved Gel Gene Deletion Goals Hemorrhage Human Immune system Immunity Immunosuppression Impairment In Vitro Inbred HRS Mice Incidence Individual Infection Inflammation Lesion Malignant Neoplasms Mediating Metabolism Methods Molecular Target Morbidity - disease rate Mus Nanodelivery Operative Surgical Procedures Oral Outcome Persons Pharmaceutical Preparations Physiological Predisposition Prevention Prevention approach Preventive Procedures Property Regimen Risk Role Ryanodine Receptor Calcium Release Channel Safety Skin Skin Cancer Skin Carcinogenesis Skin Carcinoma Sunburn System Testing Time Topical application Transgenic Mice Translating UV Radiation Exposure UV carcinogenesis UV induced UV induced DNA damage Ultraviolet B Radiation Ultraviolet Rays Vision absorption antagonist anti-cancer beta-adrenergic receptor cancer chemoprevention cancer type carcinogenesis carcinogenicity cardiovascular effects carvedilol drug candidate enantiomer human subject in vivo knockout gene melanoma mortality mouse model nano novel prevent prophylactic side effect skin cancer prevention skin damage skin organogenesis ultraviolet weapons

项目摘要

Skin cancer, particularly non-melanoma skin cancer, is by far the most common malignancy in the US. Overexposure to ultraviolet (UV) radiation is a main factor causing skin cancer, via inducing DNA damage, inflammation, and immunosuppression. The β-adrenergic receptor (β-AR) antagonist (β-blocker) carvedilol, a commonly used drug for cardiovascular disorders, has shown promising activity in preventing UV-induced skin cancer in vitro and in vivo. However, as a highly potent β-blocker, systemic absorbtion of carvedilol may cause unwanted cardiovascular effects such as bradycardia and hypotention. To overcome this obstacle, two strategies are applied: (1) development of a skin targeting nanodelivery system, and (2) examination of the effects of the non-β-blocking R-carvedilol enantiomer, because carvedilol is a racemic mixture consisting of the β-blocking S- carvedilol and non-β-blocking R-carvedilol in 1:1 ratio. Preliminary data indicate that topical delivery of carvedilol loaded nano-transfersome was able to effectively prevent skin cancer without systemic absorption. Additional data indicate that β-blockade is dispensable for carvedilol's cancer preventive activity. Further preliminary studies indicate that R-carvedilol, although not a β-blocker, is effective in preventing UV-induced immunosuppression and skin carcinogenesis without affecting blood pressure. Importantly, both R- and S- carvedilol inhibit ryanodine receptors (RyRs) by reducing the opening time of this intracellular calcium channel, and further preliminary data suggest that reducing RyR opening activity represents a previously unexplored mechanism for skin cancer prevention. Thus, the overall objective of this application is to determine the molecular target for carvedilol-mediated chemoprevention and examine a novel nanodelivery system of R- carvedilol as an effective and safe approach for skin cancer prevention. Aim 1 is to test the hypothesis that carvedilol prevents cancer independently of β-blockade. Aim 2 is to test the hypothesis that reducing RyR activity mediates carvedilol's cancer preventative activity. Aim 3 is test the hypothesis that R-carvedilol can be formulated in nano-transfersome gel which can be safely and repeatedly applied to the skin without significant systemic absorption. Since carvedilol is an FDA-approved agent, we anticipate the outcomes from this project will be readily translated into a cancer preventive regimen for healthy human subjects or individuals with weakened immune system. Importantly, R-carvedilol, lacking β-blocking activity, is expected to prevent cancer without cardiovascular disturbance, and therefore should be an excellent drug for skin cancer chemoprevention.

皮肤癌，特别是非黑色素瘤皮肤癌，是迄今为止美国最常见的恶性肿瘤。过度暴露于紫外线 (UV) 辐射是导致皮肤癌的主要因素，它会诱发 DNA 损伤，炎症和免疫抑制 β-肾上腺素受体 (β-AR) 拮抗剂（β-阻滞剂）卡维地洛，一种治疗心血管疾病的常用药物，在预防紫外线引起的皮肤方面显示出良好的活性然而，作为一种高效的 β 受体阻滞剂，卡维地洛的全身吸收可能会导致癌症。不良的心血管影响，如心动过缓和低血压，要克服这一障碍，有两种策略。应用：（1）开发皮肤靶向纳米递送系统，以及（2）检查纳米递送系统的效果非β-阻断R-卡维地洛对映体，因为卡维地洛是由β-阻断S-组成的种族混合物卡维地洛和非β-阻断型R-卡维地洛的比例为1:1，初步数据表明局部给药。卡维地洛负载的纳米转移体能够有效预防皮肤癌，且无需全身吸收。其他数据表明，β-阻断对于卡维地洛的癌症预防活性来说是可有可无的。初步研究表明，R-卡维地洛虽然不是 β 阻滞剂，但可有效预防紫外线引起的重要的是，R-和S-都不会影响血压。卡维地洛通过减少细胞内钙通道的开放时间来抑制兰尼碱受体（RyRs），进一步的初步数据表明，减少 RyR 开放活动代表了以前未探索过的因此，本申请的总体目标是确定皮肤癌预防的机制。卡维地洛介导的化学预防的分子靶标并检查 R-的新型纳米递送系统卡维地洛作为一种有效且安全的皮肤癌预防方法，目标 1 是检验以下假设：卡维地洛独立于 β-阻滞剂预防癌症目的 2 是检验降低 RyR 活性的假设。介导卡维地洛的癌症预防活性目标 3 是检验 R-卡维地洛可以预防癌症的假设。采用纳米转移体凝胶配制而成，可以安全、重复地涂抹到皮肤上，而不会产生明显的影响由于卡维地洛是 FDA 批准的药物，我们预计该项目的结果。将很容易转化为健康人类受试者或患有癌症的个体的癌症预防方案重要的是，缺乏β-阻断活性的R-卡维地洛有望预防癌症。无心血管干扰，因此应该是皮肤癌化学预防的优良药物。