Skin Cancer Chemoprevention by Silibinin: Mechanisms and Efficacy

项目摘要 基底细胞癌（BCC）最重要的风险因素，约占400万新发病例 每年，是太阳紫外线B辐射（UVB）暴露。BCC的关键分子特征之一 是通过灭活肿瘤抑制基因突变持续激活刺猬（Hh）途径， 基因Ptch或Smoothened（SMO）中的激活突变。因此，已经作出了广泛的努力， 靶向激活的Hh通路治疗BCC，但存在毒副作用和耐药性。 由于这些限制，最近的研究也集中在化学预防策略，以管理 BCC。在父母补助金的具体目标I中，我们建议确定局部给药的预防效果。 水飞蓟宾在a）慢性UVB诱导的宏观BCC形成以及B） UVB诱导的显微BCC病变进展为更晚期的BCC形式。特别是 这些研究的结果（在父母补助金中）表明，局部施用水飞蓟宾 对BCC生长和进展的显著保护作用（pl.参见疗效结局 部分，B5：图1-4）。鉴于这些重要的发现，在我们完成的研究，在家长补助金和 事实上，当给予水飞蓟宾时， 口服（灌胃和/或饮食喂养）用于其他癌症[包括皮肤鳞状细胞癌 （SCC）]，当给予水飞蓟宾时，也有令人信服的可能性阻止BCC进展 口头上。这些研究没有在父母补助金中提出，但（根据我们完成的 研究）值得详细调查，并构成本补充的基础;我们预计类似的 使用口服水飞蓟宾剂量的保护作用。此外， 口服施用水飞蓟宾对抗BCC从“微观”到“宏观”等级的进展将突出显示 水飞蓟宾在预防和干预基底细胞癌方面的巨大潜力 进展我们的目的是：I）确定口服水飞蓟宾对大鼠的预防效果， UVB诱导的显微BCC病变进展为更晚期形式的BCC;和II） 确定水飞蓟宾的BCC化学预防功效的潜在生物标志物;具体地， 水飞蓟宾相关的基因表达生物标志物，并将它们与观察到的效果相关联。 考虑到水飞蓟宾作为一种广泛消费的膳食补充剂， 补充在世界各地，被认为是非常安全的，这个补充建议 是非常重要的，因为从拟议的目标成功的结果将有强大的翻译 对BCC的预防和干预具有重要意义。

Project Summary Abstract The most important risk factor for basal cell carcinoma (BCC), accounting for ~4 million new cases each year, is solar ultraviolet B radiation (UVB) exposure. One of the key molecular features of BCC is sustained activation of hedgehog (Hh) pathway through inactivating mutations in tumor suppressor gene Ptch or activating mutations in Smoothened (SMO). Consequently, extensive efforts have been made to target activated Hh pathway to treat BCC, though with toxic side effects and drug resistance. Due to these limitations, recent studies have also focused on chemopreventive strategies to manage BCC. In specific Aim I of the parent grant, we proposed to determine the preventive efficacy of topical application of silibinin on a) chronic UVB-induced macroscopic BCC formation as well as b) on the progression of UVB-induced microscopic BCC lesions to more advanced forms of BCCs. Notably, the outcomes from these studies (in the parent grant) have shown that topical silibinin application has significant protective effects against BCC growth and progression (pl. refer to efficacy outcomes section, B5: Fig 1-4). Given these important findings in our completed studies in the parent grant and the fact that silibinin has also shown strong chemopreventive and anti-cancer potential when given orally (by gavage and/or dietary feeding) in other cancers [including skin squamous cell carcinoma (SCC)], there is a compelling likelihood that silibinin would also prevent BCC progression when given orally. Such studies were not proposed in the parent grant, but (based on our completed studies) merit detailed investigation and forms the basis of this supplement; we expect similar protective effects using oral silibinin dosing in our proposed studies. Also, the anticipated efficacy of orally administered silibinin against BCC progression from ‘micro’ to ‘macro’ grade will highlight the tremendous potential of silibinin for its preventive and interventive applications against BCC progression. Our aims are: I) to determine the preventive efficacy of oral feeding of silibinin on the progression of UVB-induced microscopic BCC lesions to more advanced forms of BCCs; and II) to determine potential biomarkers of BCC chemopreventive efficacy of silibinin; specifically, to identify silibinin-associated gene expression biomarkers and correlate them with the observed effects. Considering that silibinin has a long history of human use as a widely consumed dietary supplement around the world and is considered exceptionally safe, this supplement proposal is highly significant as successful results from proposed aims would have strong translational implications in the prevention and intervention of BCC.