Chemoprevention by Black Raspberry of Oral Cancer Induced by Tobacco Carcinogens: Translational Studies

黑树莓对烟草致癌物诱发的口腔癌的化学预防：转化研究

基本信息

批准号：
9885149
负责人：
KARAM E EL-BAYOUMY
金额：
$ 34.43万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9885149
关键词：
Allelic Imbalance Anthocyanins Antioxidants Aromatic Polycyclic Hydrocarbons Base Excision Repairs Benzo(a)pyrene Biological Assay Carcinogens Cells Chemoprevention Chemopreventive Agent Clinical Trials Cohort Studies DNA Adducts DNA Damage DNA Repair DNA Repair Enzymes DNA Structure DNA lesion Data Deoxyribonucleotides Development Dietary Intervention Disease Eating Enteral Environment Environmental Carcinogens Environmental Exposure Enzymes Epithelial Epithelium Epoxy Compounds Etiology Event Excision Exposure to Freeze Drying Future Gel Gene Mutation Glutathione Disulfide Glycols Head and Neck Cancer Heterogeneity Human In Vitro Intervention Knock-out Literature Loss of Heterozygosity Malignant Epithelial Cell Minerals Molecular Mus Mutagenesis Mutation N&apos -nitrosonornicotine NADP Nitrosamines Nucleotide Excision Repair OGG1 gene Oral Oral Leukoplakia Oral cavity Oral mucous membrane structure Oxidation-Reduction Participant Patients Phase Phenols Powder dose form Prevention Prevention approach Pyrenes Raspberries Reaction Recycling Reduced Glutathione Ribonucleotides Risk Factors Role Scheme Smoker Structure Surface TP53 gene Time Tissues Tobacco Tobacco smoke Tobacco smoking behavior Tobacco use Tobacco-Associated Carcinogen Tobacco-Related Carcinoma Topical application Tumor Suppressor Genes Voice Xenobiotic Metabolism adduct base carcinogenesis cofactor design disorder control drinking environmental tobacco smoke foodborne genomic locus high risk insight keratinocyte malignant mouth neoplasm mouse model mouth squamous cell carcinoma multimodality novel oxidative DNA damage oxidative damage preservation prevent public health relevance repair enzyme repaired smoking cessation targeted treatment translational study

项目摘要

Project Abstract Tobacco use remains a high risk factor for oral squamous cell carcinoma (OSCC) resulting from exposure to potent tobacco carcinogens including polycyclic aromatic hydrocarbons (PAHs) such as dibenzo[a,l]pyrene (DB[a,l]P), benzo[a]pyrene (B[a]P) and tobacco-specific nitrosamines (TSNA) such as N’-nitrosonornicotine (NNN). To assess effects of these carcinogens on oral mucosa, we developed a novel OSCC mouse model using DB[a,l]P and its fjord region diol epoxide (DB[a,l]PDE). Importantly, we showed that dietary intervention with freeze-dried black raspberries (BRB) powder inhibited carcinogen-induced DNA damage, mutagenesis and carcinogenesis in the mouse oral cavity. We have also established that BRB reduce formation and/or enhance repair of bulky adducts in vitro, but, the mechanisms by which BRB reduce DNA damage remain to be fully elucidated. Considering the varied structures of DNA adducts, we will focus on BRB effects on the nucleotide excision repair (NER) and base-excision repair (BER) enzymes. Based on the abundant phenolic compounds in BRB e.g. anthocyanins, it is logical to propose that BRB help preserve the cellular redox poise, enhance redox scavenging and thus function to prevent oxidative DNA damage; our data support this proposition. In addition to their cytoprotective functions, a specific cellular reducing equivalent-NADPH-functions in reductive biosynthetic reactions including conversion of ribonucleotides to deoxyribonucleotides (dNTPs) that are essential components for DNA repair. Based on these data, we hypothesize that BRB reduce DNA damage (cf. Scheme 1, Significance) in a multimodal fashion: 1) BRB enhance NER and BER function via preservation of key substrates and cofactors i.e. dNTPs and Mg2+, while maintaining an optimal, non-oxidized environment conducive to DNA repair; 2) BRB preserve the cellular redox status via efficient scavenging of reactive species that can inhibit DNA repair enzymes thereby reducing oxidative DNA damage. The proposed mechanistic studies entail two complementary, yet independent, Specific Aims: Aim 1A will investigate the effects of BRB on repair (NER, BER) of covalent tobacco carcinogen-DNA adducts and 8-OXO-dG in primary human oral keratinocyte cells that have been transfected with these adducts using our established assay. Aim 1B will determine the capacity of BRB to prevent oxidative damage in wild-type (OGG1+/+, a component of BER enzymes) and knockout (OGG1-/-) MEF cells. Concurrent studies, applicable to both subaims, will assess BRB effect on preservation of dNTP pools and key cellular redox poise parameters in a continuum of validated cells ranging from primary human oral keratinocytes, oral leukoplakia and OSCC cells. Aim 2 will determine for the first time the effects of local BRB delivery on formation of covalent DNA adducts and 8-OXO-dG in buccal cells of healthy smokers. The results could serve as the framework for future chemopreventive trials for addicted smokers who are unable to quit as well as non- or former-smokers who are exposed to environmental carcinogens.

项目摘要吸烟仍然是口腔鳞状细胞癌 (OSCC) 的高危因素强效烟草致癌物，包括多环芳烃 (PAH)，例如二苯并[a,l]芘 (DB[a,l]P)、苯并[a]芘 (B[a]P) 和烟草特有的亚硝胺 (TSNA)，例如 N'-亚硝基降烟碱 (NNN)。为了评估这些致癌物对口腔粘膜的影响，我们开发了一种新型 OSCC 小鼠模型。使用 DB[a,l]P 及其峡湾地区二醇环氧化物 (DB[a,l]PDE) 重要的是，我们证明了饮食干预。冻干黑树莓 (BRB) 粉末可抑制致癌物引起的 DNA 损伤、诱变和我们还确定 BRB 会减少和/或增强小鼠口腔的致癌作用。体外修复大体积加合物，但是，BRB 减少 DNA 损伤的机制仍有待充分研究考虑到 DNA 加合物的不同结构，我们将重点关注 BRB 对核苷酸的影响。基于丰富的酚类化合物的切除修复（NER）和碱基切除修复（BER）酶。在 BRB 中，例如花青素，可以合理地认为 BRB 有助于保持细胞氧化还原平衡，增强氧化还原清除作用，从而防止 DNA 氧化损伤；此外，我们的数据也支持这一观点。其细胞保护功能，还原中的特定细胞还原等效 NADPH 功能生物合成反应，包括将核糖核苷酸转化为必需的脱氧核糖核苷酸 (dNTP) 基于这些数据，我们寻求 BRB 减少 DNA 损伤（参见方案 1，意义）以多模式方式：1）BRB 通过保留增强 NER 和 BER 功能关键底物和辅因子，即 dNTP 和 Mg2+，同时保持最佳的非氧化环境 2) BRB 通过有效清除活性物质来保持细胞氧化还原状态可以抑制 DNA 修复酶，从而减少 DNA 氧化损伤。研究需要两个互补但独立的具体目标：目标 1A 将调查 BRB 的影响原代人体内共价烟草致癌物-DNA 加合物和 8-OXO-dG 的修复（NER、BER）使用我们建立的检测方法，用这些加合物转染口腔角质形成细胞。 1B 将确定 BRB 防止野生型氧化损伤的能力（OGG1+/+，一种成分） BER 酶）和敲除（OGG1-/-）MEF 细胞同时进行的研究将适用于这两个子目标。评估 BRB 对 dNTP 库和关键细胞氧化还原平衡参数的连续保存的影响经验证的细胞范围包括原代人口腔角质形成细胞、口腔白斑和 OSCC 细胞 Aim 2。首次确定局部 BRB 递送对共价 DNA 加合物形成的影响健康吸烟者口腔细胞中的 8-OXO-dG 结果可作为未来的框架。针对无法戒烟的烟瘾者以及有烟瘾的非吸烟者或前吸烟者进行化学预防试验接触环境致癌物质。