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

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。 过度暴露在紫外线(UV)辐射下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阻滞剂)卡维地洛，a 治疗心血管疾病的常用药物，在预防紫外线诱导的皮肤方面显示出良好的活性 体内和体外的癌症。然而，作为一种高效的β阻滞剂，卡维地洛的全身吸收可能会导致 不想要的心血管效应，如心动过缓和低血压。要克服这一障碍，有两个策略 应用：(1)开发皮肤靶向纳米递送系统，以及(2)检查 非β封闭的R-卡维地洛对映体，因为卡维地洛是由β封闭的S组成的外消旋混合物- 卡维地洛与非β阻滞剂R-卡维地洛的比例为1：1。初步数据显示，局部给药 卡维地洛纳米转运体无需全身吸收即可有效预防皮肤癌。 更多的数据表明，β阻断对于卡维地洛的癌症预防活动是必不可少的。进一步 初步研究表明，R-卡维地洛虽然不是β阻滞剂，但在预防紫外线诱导方面有效 免疫抑制和皮肤癌，不影响血压。重要的是，R-和S- 卡维地洛通过减少细胞内钙通道的开放时间来抑制兰尼定受体(RyRs)， 进一步的初步数据表明，减少RyR的开放活动是以前未曾探索过的 预防皮肤癌的机制。因此，此应用程序的总体目标是确定 卡维地洛介导的化学预防的分子靶点及其新型纳米递送系统的研究 卡维地洛是一种有效而安全的皮肤癌预防方法。目标1是检验假设 卡维地洛可独立于β阻滞剂预防癌症。目标2是检验减少RyR活性的假设 调节卡维地洛的抗癌活性。目标3是检验R-卡维地洛可以 采用纳米转运体凝胶配方，可安全反复涂抹在皮肤上，不会有明显的 全身吸收。由于卡维地洛是FDA批准的药物，我们期待着这个项目的结果 将很容易转化为癌症预防方案，适用于健康的人类受试者或患有 免疫系统减弱。重要的是，缺乏β阻断活性的R-卡维地洛有望预防癌症 没有心血管障碍，因此应该是一种很好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.