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

• 批准号: 10418263
• 负责人: Ying Huang
• 金额: $ 32.25万
• 依托单位: WESTERN UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10418263
• 关键词: AR gene; Adrenergic Antagonists; Affect; Applications Grants; Attenuated; 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; Lead; Lesion; Malignant Neoplasms; Mediating; Metabolism; Methods; Molecular Target; Morbidity - disease rate; Mus; Nano delivery; Operative Surgical Procedures; Oral; Outcome; Persons; Pharmaceutical Preparations; Physiological; Predisposition; Prevention; Prevention approach; Preventive; Procedures; Property; Regimen; Risk; Role; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Safety; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Sunburn; System; Testing; The Sun; Time; Topical application; Transgenic Mice; Translating; UV carcinogenesis; UV induced; UV induced DNA damage; Ultraviolet B Radiation; Ultraviolet Rays; Vision; absorption; antagonist; anti-cancer; base; beta-adrenergic receptor; cancer chemoprevention; 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

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，尤其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，通过诱导的DNA损伤， 炎症和免疫抑制。 β-肾上腺素能受体（β-AR）拮抗剂（β受体阻滞剂）卡丝醇，A 通常用于心血管疾病的药物，在防止紫外线诱导的皮肤方面表现出了有希望的活动 体外和体内癌症。然而，作为高度潜在的β受体阻滞剂，卡维地醇的全身吸收可能会导致 心血管疾病等不需要的心血管效应。为了克服这一障碍，两种策略 应用：（1）开发靶向纳米递送系统的皮肤，以及（2）检查 非β障碍物R-carvedilol对映异构体，因为卡维地醇是一种外围混合物，由β受体阻滞S-组成 Carvedilol和非β障碍物R-固定酚的比例为1：1。初步数据，表明局部交付 卡维丝洛尔（Carvedilol）装载的纳米转移剂能够有效预防皮肤癌，而无需全身滥用。 其他数据表明β-阻滞剂对于卡维迪尔的癌症预防活性是可分配的。更远 初步研究表明，r-核深酚虽然不是β受体阻滞剂，但可有效防止紫外线诱导 免疫抑制和皮肤致癌而不会影响血压。重要的是，r-和s- 卡维地洛（Carvedilol 进一步的初步数据表明，减少RYR开放活动代表以前出乎意料的 预防皮肤癌的机制。这，本应用程序的总体目的是确定 用于凯具有凯藤洛尔介导的化学预防和检查的分子靶标 卡维丝醇作为预防皮肤癌的有效方法。目的1是检验以下假设 卡维地醇可防止癌症独立于β阻滞。 AIM 2是测试降低RYR活性的假设 介导卡维地（Carvedilol）的癌症预防活性。 AIM 3是测试R-核层醇的假设 在纳米转换凝胶中锻造，可以安全地涂在皮肤上而无需明显的皮肤 系统性滥用。由于Carvedilol是FDA批准的代理商，我们预计该项目的结果 对于健康的人类受试者或患有患者的人 免疫抑制系统减弱。重要的是，缺乏β受体阻滞活性的R型carvedilol有望预防癌症 没有心血管灾难，因此应该是皮肤癌化学预防的出色药物。