Chemoprotective role of silver nanoparticles in UV radiation-induced skin carcino

银纳米粒子在紫外线辐射诱发的皮肤癌中的化学保护作用

• 批准号: 8704599
• 负责人: Seema Singh
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704599
• 关键词: Accounting; Adverse effects; Apoptosis; Base Excision Repairs; Benign; Biochemical; Biological Assay; Biological Markers; Biological Models; Carbopol; Cell Cycle Arrest; Cells; Chemopreventive Agent; Chemoprotection; Chemoprotective Agent; Chronic; Clinical Data; Colon Carcinoma; Cytosine; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Deletion Mutation; Development; Drug Formulations; Epidemiology; Exposure to; Future; Gel; Generations; Human; Hydrogen Peroxide; Hydroxyl Radical; In Vitro; Inbred HRS Mice; Incidence; Inhibition of Apoptosis; Injury; Investigation; Lead; Lesion; Light; Malignant - descriptor; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Molecular; Mus; Mutation; Nucleotide Excision Repair; Nucleotides; Outcome; Pathway interactions; Pilot Projects; Porphyrins; Premalignant; Prevention strategy; Preventive; Production; Proteins; Purines; Pyrimidine Dimers; Reactive Oxygen Species; Reporting; Research; Riboflavin; Risk; Role; S Phase; Safety; Silver; Skin; Skin Cancer; Skin Carcinogenesis; Sterility; Sunburn; Sunscreening Agents; Supplementation; Testing; The Sun; Thymine Dimers; Time; Tryptophan; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Zinc Oxide; base; carcinogenesis; combat; crosslink; design; improved; in vivo; inhibitor/antagonist; innovation; insight; keratinocyte; malignant breast neoplasm; mouse model; nanoparticle; novel; oxidative DNA damage; particle; pre-clinical; protective effect; public health relevance; purine; small molecule; titanium dioxide; ultraviolet

DESCRIPTION (provided by applicant): Each year, there are more new cases of skin cancer than the combined incidence of breast, prostate, lung and colon cancers, which clearly emphasizes the need for the development of effective prevention strategies. Ultraviolet (UV) radiation from sun, particularly its UVB component, is the most established epidemiological cause of skin cancer. UVB radiation causes DNA damage, which if remained unrepaired ultimately leads to accumulation of carcinogenic mutations and subsequent malignant transformation. Currently, several topical sunscreen formulations are being used for protection against UV radiation-induced skin injury and carcinogenesis; however, none seem to be very much effective and incidence of skin cancer continues to rise every coming year. This proposal is based on our novel findings demonstrating that the pretreatment of human immortalized keratinocytes (HaCaT) with silver nanoparticles (AgNPs): i) leads to reduced formation of cyclobutane pyrimidine dimers (CPDs) upon exposure to UVB radiation, ii) protects the HaCaT keratinocytes from UVB radiation-induced apoptosis, iii) suppresses basal as well as UVB-induced ROS production, and iv) induces cell cycle arrest in G1/S phase. Based on these promising findings, we hypothesize that Silver nanoparticles (AgNPs) are effective chemopreventive agents against UVB-induced skin injury and carcinogenesis. The overall objective of this pilot proposal is to generate additional supportive data towards this hypothesis using biochemical and functional assays, which would provide strong support for the design of rigorous studies to explore the chemopreventive potential of AgNPs. Thus, we propose two complementary Specific Aims: 1) Define the molecular mechanisms underlying chemoprotective effects of silver nanoparticles against UVB radiation-induced skin carcinogenesis, and 2) Evaluate the chemoprotective efficacy of silver nanoparticles against UVB-induced skin carcinogenesis in mouse model. Studies proposed in Aim 1 will provide us mechanistic insight into the chemoprotective action of AgNPs against UVB-induced skin carcinogenesis, while those proposed in Aim 2 will provide direct pre-clinical evidence for chemoprotective efficacy of AgNPs. The outcome from the proposed pilot studies will form the bases for future investigations to develop AgNPs-based effective chemopreventive formulation(s).

描述（由申请人提供）：每年，皮肤癌的新病例比乳腺癌，前列腺，肺和结肠癌的组合发生率更多，这清楚地强调了开发有效预防策略的需求。来自太阳的紫外线（紫外线）辐射，尤其是其UVB成分，是皮肤癌最确立的流行病学原因。 UVB辐射会导致DNA损伤，如果未经修复的话，最终会导致致癌突变的积累和随后的恶性转化。目前，正在使用几种局部防晒霜制剂来防止紫外线辐射引起的皮肤损伤和致癌作用。但是，似乎没有一个非常有效，皮肤癌的发生率每年都会持续上升。该提议基于我们的新发现，表明人类永生的角质形成细胞（HACAT）用银纳米颗粒（AGNPS）（AGNP）：i）导致在暴露于UVB辐射的情况下降低环丁烷嘧啶二聚体（CPD）的形成 - iii）抑制基础和UVB诱导的ROS产生，iv）诱导G1/S期的细胞周期停滞。基于这些有希望的发现，我们假设银纳米颗粒（AGNP）是针对UVB诱导的皮肤损伤和癌变的有效化学预防剂。该试验提案的总体目的是使用生化和功能测定来生成额外的支持数据，以实现这一假设，这将为严格的研究设计提供强有力的支持，以探索AGNP的化学预防潜力。因此，我们提出了两个互补的特定目的：1）定义银纳米颗粒对化学保护作用的分子机制对UVB辐射诱导的皮肤致癌的作用，以及2）评估银纳米颗粒对UVB诱导的皮肤癌在小鼠模型中的化学保护功效。 AIM 1中提出的研究将为我们提供有关AGNP对UVB诱导的皮肤致癌作用的化学保护作用的机械洞察力，而AIM 2中提出的研究将为AGNP的化学保护功效提供直接的临床前证据。拟议的试点研究的结果将构成未来研究以开发基于AGNP的有效化学预防配方的基础。