Cancer Chemoprevention by Pomegranate Fruit Extract

描述（申请人提供）：近年来，光化学预防已成为一种公认的控制皮肤癌的方式。虽然光化学预防可以通过在皮肤致瘤性的开始或促进阶段进行干预来实现，但由于各种原因，例如可以使用防晒霜来防止紫外线（UV）辐射的渗透，抗肿瘤促进剂似乎更有可能在人体中成功。然而，寻找光化学预防装备的理想剂仍在继续。植物类黄酮类化合物是一类多酚类化合物，有望成为有效的化学预防和化学治疗药物。石榴果提取物（PFE），来源于石榴树，是两种多酚类化合物的丰富来源；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可以防止化学诱导的皮肤癌。最近，我们发现用PFE处理正常人表皮角质形成细胞（NHEK）可抑制dvb介导的ikappabα降解和磷酸化，以及IKKalpha和NFkappaB的激活。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一种新型光化学预防剂。本研究要验证的中心假设是，PFE通过阻断uvb介导的鸟氨酸脱羧酶（ODC）诱导和减少NFkappaB激活，对uvb介导的光致癌作用的发生和进展提供保护。为了验证我们的假设，我们将使用SKH-1无毛和ODC过表达的光致癌小鼠模型，这两种模型似乎都与人类皮肤癌有关。为了实现我们的目标，我们提出了三个具体目标：(i)确定口服PFE对uvb介导的癌症化学预防靶点（ODC和NFkappaB途径）以及SKH-1无毛小鼠肿瘤促进短期标记物的调节作用；（ii）确定口服PFE对uvb介导的SKH-1无毛小鼠皮肤肿瘤发生的预防潜力；（iii）研究口服PFE对uvb介导的ODC过表达小鼠皮肤肿瘤发生的影响。健康相关性：本提案旨在定义一种新的光化学预防剂，用于人类皮肤癌。

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.