Prevention of UVB-induced skin cancer using sulforaphane: roles of AP-1 and Nrf2.

使用萝卜硫素预防 UVB 诱发的皮肤癌：AP-1 和 Nrf2 的作用。

基本信息

批准号：
8320947
负责人：
Sally E Dickinson
金额：
$ 11.81万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-29 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320947
关键词：
Accounting Actinic keratosis Acute Affect American Association of Cancer Research Animals Arizona Bioethics Biological Markers Biometry Cancer Biology Cancer Center Cancer Control Cancer Model Cell Nucleus Chemicals Chemopreventive Agent Chromatin Chronic Clinical Research Clinical Trials Cream Cysteine DNA Binding DNA Binding Domain Data Development Plans Dose Double-Blind Method Drug Formulations Epidermis Exposure to Family member Forearm Genotype Goals Histopathology Human Incidence Institutes Isothiocyanates K-Series Research Career Programs Knock-out Knockout Mice Light Link Malignant Neoplasms Malignant Squamous Cell Neoplasm Measurement Mentors Methodology Modeling Molecular Mus Mutate Mutation NQO1 gene Nuclear Oxidants Oxidation-Reduction Patients Phase Phenotype Placebo Control Placebos Prevention Prevention program Program Research Project Grants Proliferation Marker Proteins Punch Biopsy Randomized Reference Standards Regulation Relative (related person)Research Personnel Risk Role Safety Sampling Scientist Skin Skin Cancer Skin Carcinogenesis Skin Carcinoma Skin Neoplasms Squamous Cell Staining method Stains Statistical Distributions Sulforaphane Testing The Sun Toxic effect Training Transactivation Transcription Factor AP-1 Transgenic Mice Tumor Burden UVB induced Ultraviolet B Radiation Work activating transcription factor anticancer research cancer chemoprevention cancer diagnosis cancer prevention carcinogenesis career development cruciferous vegetable interest keratinocyte meetings mutant oxidative DNA damage oxidative damage planetary Atmosphere prevent programs response safety study safety testing skin cancer prevention stem symposium tool transcription factor treatment duration tumor volunteer

项目摘要

DESCRIPTION (provided by applicant): Non-melanoma skin cancer (NMSC) rates are rising due to factors such as increased UVB light penetrating our atmosphere. Skin cancer, the majority of which is NMSC, accounts for nearly 40% of all diagnosed cancers in the U.S. It is my goal as a scientist to find new, applicable and affordable topical compounds which will be used to reduce the incidence of NMSC in humans. A K07 Career Development Award (CDA) is the most effective means for me to begin to accomplish these objectives and become a productive top-level cancer biologist. To accomplish this goal, I must become well-trained in cancer biology and clinical trial methodology. As part of my career development plan, I have assembled a team of outstanding mentors in skin cancer research, mouse studies, drug formulation, and clinical trials. I will have regular interactions with my mentors and will receive didactic training in subjects such as clinical trial management, bioethics, and biostatistics. I will attend AACR conferences, meetings for the Skin Cancer Program Project Grant and seminars in Cancer Prevention and Control. The Arizona Cancer Center and the Skin Cancer Institute provide me with unique and valuable tools for furthering my training and accomplishing my goals. Scientifically, this CDA will help me to examine the roles of AP-1 and Nrf2 in the mechanism of action of the chemopreventive compound sulforaphane (SF) in UVB-treated skin. SF is an isothiocyanate found in cruciferous vegetables, and inhibits carcinogenesis in several models, possibly due to induction of the transcription factor Nf E2-related factor 2 (Nrf2). Additionally, SF blocks the activity and DNA-binding ability of the activator protein-1 (AP-1) transcription factor, a key component in UVB-induced skin carcinogenesis. We hypothesize that SF inhibits DVB-induced skin carcinogenesis and will reduce the risk of squamous cell carcinogenesis in patients with sun-damaged skin through a dual mechanism of action: Nrf2 activation leading to reduced oxidative DNA damage, and AP-1 inhibition through direct redox modulation. To test this hypothesis we will 1) test whether the inhibitory effect of SF on AP-1 transactivation and skin carcinogenesis is due to chemical interactions with the DNA binding domain of cFos and/or cJun; 2) test the influence of SF- induced Nrf2 on-protection against acute UVB-induced mouse skin damage and chronic UVB-induced NMSC; 3) test the safety and efficacy of topical purified F in humans (a Phase l/lla clinical trial).

描述（由申请人提供）：由于诸如UVB光穿透我们大气的因素，非黑色素瘤皮肤癌（NMSC）率正在上升。皮肤癌（其中大多数是NMSC）占美国所有被诊断癌症的40％，这是我作为科学家的目标，是找到新的，适用和负担得起的局部化合物，这些化合物将用于减少人类NMSC的发生率。 K07职业发展奖（CDA）是我开始实现这些目标并成为一名富有成效的顶级癌症生物学家的最有效手段。为了实现这一目标，我必须在癌症生物学和临床试验方法中获得良好的训练。作为我职业发展计划的一部分，我组建了一支在皮肤癌研究，小鼠研究，药物制定和临床试验方面的杰出导师团队。我将与导师进行定期互动，并将在临床试验管理，生物伦理学和生物统计学等受试者中接受教学培训。我将参加AACR会议，针对皮肤癌计划项目赠款的会议以及预防和控制的研讨会。亚利桑那州癌症中心和皮肤癌研究所为我提供了独特而有价值的工具，以促进我的培训并实现目标。从科学上讲，该CDA将帮助我检查AP-1和NRF2在化学预防化合物磺烷（SF）在UVB处理的皮肤中的作用机理中的作用。 SF是在十字花科蔬菜中发现的异硫氰酸盐，在几种模型中抑制了癌变，这可能是由于转录因子NF E2相关因子2（NRF2）的诱导。另外，SF阻断了激活蛋白-1（AP-1）转录因子的活性和DNA结合能力，这是UVB诱导的皮肤癌变中的关键成分。我们假设SF抑制了DVB诱导的皮肤癌变，并通过双重作用机制来降低具有阳光损伤皮肤的鳞状细胞癌变的风险：NRF2激活，导致氧化性DNA损伤减少，并通过直接培养物调节抑制AP-1。为了检验该假设，我们将测试SF对AP-1反式激活和皮肤致癌作用的抑制作用是否是由于化学相互作用与CFOS和/或CJUN的DNA结合结构域的相互作用； 2）测试SF诱导的NRF2对急性UVB诱导的小鼠皮肤损伤和慢性UVB诱导的NMSC的影响； 3）测试局部纯化F在人类中的安全性和功效（一项LLA临床试验）。