Cancer Chemoprevention by Pomegranate Fruit Extract

描述（申请人提供）：近年来，光化学预防已成熟为控制皮肤癌的公认方式。虽然光化学预防可以通过在皮肤致瘤性的起始或促进阶段进行干预来实现，但出于各种原因，例如防晒剂的可用性以防止紫外线（UV）辐射的渗透，抗肿瘤促进剂似乎在人类中具有更大的成功可能性。然而，对用于光化学预防的医疗设备的理想试剂的研究仍在继续。植物类黄酮是一组多酚类化合物，具有良好的化学预防和化学治疗作用。石榴果提取物（PFE），来自石榴树，是两种类型的多酚化合物的丰富来源;花青素和水解单宁，并具有有效的抗氧化和抗炎特性。最近，我们已经证明，局部应用PFE防止化学诱导的皮肤癌发生。最近，我们发现用PFE处理正常人表皮角质形成细胞（NHEK）抑制DVB介导的IkappaB α的降解和磷酸化、IKK α和NF κ B的活化。根据这些数据和其他已发表的研究，PFE或其中存在的成分很有可能被开发为新型光化学预防剂。在这个建议中要测试的中心假设是，PFE将提供保护，防止UVB介导的光致癌作用的发展和进展，通过阻断UVB介导的鸟氨酸脱羧酶（ODC）的诱导和减少NF κ B的激活。为了验证我们的假设，我们将采用SKH-1无毛和ODC过表达小鼠模型的光致癌作用，这两个似乎有相关的人类皮肤癌。为了实现我们的目标，提出了三个具体目标：（i）在SKH-1无毛小鼠中确定口服PFE对UVB介导的癌症化学预防靶点即ODC和NF κ B途径的调节以及肿瘤促进的短期标志物的影响，（ii）在SKH-1无毛小鼠中建立PFE对UVB介导的皮肤肿瘤发生的预防潜力，（iii）研究口服PFE对UVB引发的ODC过表达小鼠皮肤肿瘤发生的影响。健康相关性：该提案旨在定义一种可能用于人类的新型皮肤癌光化学预防剂。

DESCRIPTION (provided by applicant): In recent years photochemoprevention has matured into an accepted modality for controlling skin cancer. Although photochemoprevention can be achieved by intervention at initiation or promotion phases of skin tumorigenicity, for a variety of reasons, for example availability of sunscreens to prevent penetration of ultraviolet (UV) radiation, anti-tumor promoting agents appear to have greater likelihood for success in human. However, the search for ideal agent(s) for the armamentarium of photochemoprevention continues. Plant-based flavonoids, a group of polyphenolic compounds, are showing promise as useful chemo- preventive and chemotherapeutic agents. Pomegranate fruit extract (PFE), derived from the tree of Punica granatum, is a rich source of two types of polyphenolic compounds; anthocyanins and hydrolyzable tannins, and possesses potent antioxidant and anti-inflammatory properties. Recently we have demonstrated that topical application of PFE prevents chemically induced skin carcinogenesis. More recently, we found that the treatment of normal human epidermal keratinocytes (NHEK) with PFE inhibits DVB-mediated degradation and phosphorylation of IkappaBalpha, activation of IKKalpha and NFkappaB. In light of these data and other published studies there is a strong possibility that PFE or constituent(s) present therein may be developed as a novel photochemopreventive agent. The central hypothesis to be tested in this proposal is that PFE will afford protection against the development and progression of UVB-mediated photocarcinogenesis by blocking UVB-mediated ornithine decarboxylase (ODC) induction and by reducing NFkappaB activation. To test our hypothesis we will employ SKH-1 hairless and ODC overexpressing mouse models of photocarcinogenesis both of which appears to have relevance to human skin cancer. To accomplish our goals three specific aims are proposed: (i) to determine the effect of oral feeding of PFE on UVB-mediated modulation in cancer chemopreventive targets viz. ODC and NFkappaB pathway, and short-term markers of tumor promotion in SKH-1 hairless mice, (ii) to establish the preventive potential of PFE against UVB-mediated skin tumorigenesis in SKH-1 hairless mice and, (iii) to study the effect of oral feeding of PFE on UVB-initiated skin tumorigenesis in ODC overexpressing mice. HEALTH RELEVANCE: This proposal intends to define a novel photochemo- preventive agent against skin cancer for its possible use in humans.