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

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，通过诱导DNA损伤， 炎症和免疫抑制。β-肾上腺素能受体（β-AR）拮抗剂（β-阻断剂）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病方面显示出有希望的活性。 癌症在体外和体内。然而，卡维地洛作为一种高效的β-受体阻滞剂，其全身吸收可能导致 不必要的心血管效应，如心动过缓和震颤。为了克服这一障碍，我们采取了两个策略。 应用：（1）皮肤靶向纳米递送系统的开发，和（2）检查 非β-阻断R-卡维地洛对映体，因为卡维地洛是由β-阻断S- 卡维地洛和非β-阻断R-卡维地洛的比例为1：1。初步数据表明，局部给药 载卡维地洛的纳米转移体能够有效地预防皮肤癌，而没有全身吸收。 其他数据表明，β-阻断剂对卡维地洛的癌症预防活性是不利的。进一步 初步研究表明，R-卡维地洛虽然不是β-受体阻滞剂，但在预防紫外线诱导的 免疫抑制和皮肤癌发生而不影响血压。重要的是，R-和S- 卡维地洛通过减少这种细胞内钙通道的开放时间来抑制兰尼碱受体（RyR）， 进一步的初步数据表明，减少RyR开放活性代表了一个以前未探索的 皮肤癌的预防机制。因此，本申请的总体目标是确定 卡维地洛介导的化学预防的分子靶点，并检查一种新的R- 卡维地洛是一种有效和安全的预防皮肤癌的方法。目的1是检验假设， 卡维地洛不依赖于β-阻断剂而预防癌症。目的2是检验降低RyR活性 介导卡维地洛的癌症预防活性。目的3：验证R-卡维地洛可作为 配制成纳米转移体凝胶，可以安全地重复应用于皮肤， 全身吸收由于卡维地洛是FDA批准的药物，因此我们预计该项目的结果 将容易地转化为用于健康人类受试者或患有以下疾病的个体的癌症预防方案： 削弱免疫系统。重要的是，缺乏β-阻断活性的R-卡维地洛有望预防癌症 无心血管功能障碍，是一种理想的皮肤癌化学预防药物。

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.